PYRAZOLO[3,4-d]PYRIMIDINE COMPOUNDS, THEIR PREPARATION AND USE AS SIGMA LIGANDS

ABSTRACT

New pyrazolo[3,4-d]pyrimidine compounds having a great affinity for sigma receptors, especially sigma-1 receptors, as well as to the process for preparing these compounds, to compositions comprising them and to their use as medicaments.

FIELD OF THE INVENTION

The present invention relates to new pyrazolo[3,4-d]pyrimidine compoundshaving a great affinity for sigma receptors, especially sigma-1receptors as well as to the process for the preparation thereof, tocomposition comprising them and to their use as medicaments.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by better understanding of the structure of proteins and otherbiomolecules associated with target diseases. One important class ofthese proteins are the sigma (a) receptors, cell surface receptors ofthe central nervous system (CNS) which may be related to the dysphoric,hallucinogenic and cardiac stimulant effects of opioids. From studies ofthe biology and function of sigma receptors, evidence has been presentedthat sigma receptor ligands may be useful in the treatment of psychosisand movement disorders such as dystonia and tardive dyskinesia, andmotor disturbances associated with Huntington's chorea or Tourette'ssyndrome and in Parkinson's disease (Walker, J. M. et al,Pharmacological Reviews, 1990, 42, 355). It has been reported that theknown sigma receptor ligand rimcazole clinically shows effects in thetreatment of psychosis (Snyder, S. H., Largent, B. L. J. Neuropsychiatry1989, 1, 7). The sigma binding sites have preferential affinity for thedextrorotatory isomers of certain opiate benzomorphans, such as(+)-SKF-10047, (+)-cyclazocine, and (+)-pentazocine and also for somenarcoleptics such as haloperidol.

“The sigma receptor/s” as used in this application is/are well known anddefined using the following citation: This binding site represents atypical protein different from opioid, NMDA, dopaminergic, and otherknown neurotransmitter or hormone receptor families (G. Ronsisvalle etal. Pure Appl. Chem. 73, 1499-1509 (2001)).

The sigma receptor has at least two subtypes, which may be discriminatedby stereoselective isomers of these pharmacoactive drugs. SKF-10047 hasnanomolar affinity for the sigma 1 (σ-1) site, and has micromolaraffinity for the sigma 2 (σ-2) site. Haloperidol has similar affinitiesfor both subtypes.

The Sigma-1 receptor is a non-opiaceous type receptor expressed innumerous adult mammal tissues (central nervous system, ovary, testicle,placenta, adrenal gland, spleen, liver, kidney, gastrointestinal tract,etc.) as well as in embryo development from its earliest stages, and isapparently involved in a large number of physiological functions. Itshigh affinity for various pharmaceuticals has been described, such asfor SKF-10047, (+)-pentazocine, haloperidol and rimcazole, among others,known ligands with analgesic, anxiolytic, antidepressive, antiamnesic,antipsychotic and neuroprotective activity. The sigma-1 receptor is ofgreat interest in pharmacology in view of its possible physiologicalrole in processes related to analgesia, anxiety, addiction, amnesia,depression, schizophrenia, stress, neuroprotection and psychosis [Kaiseret al (1991) Neurotransmissions 7 (1): 1-5], [Walker, J. M. et al,Pharmacological Reviews, 1990, 42, 355] and [Bowen W. D. (2000)Pharmaceutica Acta Helvetiae 74: 211-218].

The Sigma-2 receptor is also expressed in numerous adult mammal tissues(nervous system, immune system, endocrine system, liver, kidney, etc.).Sigma-2 receptors can be components in a new apoptosis route that mayplay an important role in regulating cell proliferation or in celldevelopment. This route seems to consist of Sigma-2 receptors joined tointracellular membranes, located in organelles storing calcium, such asthe endoplasmic reticulum and mitochondria, which also have the abilityto release calcium from these organelles. The calcium signals can beused in the signalling route for normal cells and/or in induction ofapoptosis.

Agonists of Sigma-2 receptors induce changes in cell morphology,apoptosis in several types of cell lines and regulate the expression ofp-glycoprotein mRNA, so that they are potentially useful asantineoplasic agents for treatment of cancer. In fact, Sigma-2 receptoragonists have been observed to induce apoptosis in mammary tumour celllines resistant to common antineoplasic agents that damage the DNA. Inaddition, agonists of Sigma-2 receptors enhance the cytotoxic effects ofthese antineoplasic agents at concentrations in which the agonist is notcytotoxic. Thus, agonists of Sigma-2 receptors can be used asantineoplasic agents at doses inducing apoptosis or at sub-toxic dosesin combination with other antineoplasic agents to revert the resistanceto the drug, thereby allowing using lower doses of the antineoplasicagent and considerably reducing its adverse effects.

Antagonists of Sigma-2 receptors can prevent the irreversible motor sideeffects caused by typical neuroleptic agents. In fact, it has been foundthat antagonists of Sigma-2 receptors can be useful as agents forimproving the weakening effects of delayed dyskinesia appearing inpatients due to chronic treatment of psychosis with typicalantipsychotic drugs, such as haloperidol. Sigma-2 receptors also seem toplay a role in certain degenerative disorders in which blocking thesereceptors could be useful.

Endogenous sigma ligands are not known, although progesterone has beensuggested to be one of them. Possible sigma-site-mediated drug effectsinclude modulation of glutamate receptor function, neurotransmitterresponse, neuroprotection, behavior, and cognition (Quirion, R. et al.Trends Pharmacol. Sci., 1992, 13:85-86). Most studies have implied thatsigma binding sites (receptors) are plasmalemmal elements of the signaltransduction cascade. Drugs reported to be selective sigma ligands havebeen evaluated as antipsychotics (Hanner, M. et al. Proc. Natl. Acad.Sci., 1996, 93:8072-8077). The existence of sigma receptors in the CNS,immune and endocrine systems have suggested a likelihood that it mayserve as link between the three systems.

In view of the potential therapeutic applications of agonists orantagonists of the sigma receptor, a great effort has been directed tofind selective ligands. Thus, the prior art discloses different sigmareceptor ligands.

For instance, the international patent application WO2007/098961describes 4,5,6,7 tetrahydrobenzo[b]thiophene derivatives havingpharmacological activity towards the sigma receptor.

Spiro[benzopyran] or spiro[benzofuran] derivatives were also disclosedin EP1847542 as well as pyrazole derivatives (EP1634873) withpharmacological activity on sigma receptors.

WO 2008049105 discloses some pyrazolo[3,4-d]pyrimidine compounds butthey are rather inhibitors of Heat Shock Protein 90 (HSP90) and usefulto treat disorders mediated by HSP90.

There is still a need to find compounds having pharmacological activitytowards the sigma receptor, being both effective and selective, andhaving good “drugability” properties, i.e. good pharmaceuticalproperties related to administration, distribution, metabolism andexcretion.

SUMMARY OF THE INVENTION

The present invention discloses novel compounds with great affinity tosigma receptors which might be used for the treatment of sigma relateddisorders or diseases.

Specifically, it is an object of the present invention novelpyrazolo[3,4-d]pyrimidine compounds of general formula (I):

where R₁, R₂, R₃ and R₄ are as described below.

It is also an object of the invention different processes for theirpreparation, including a process for preparing enantiomerically purecompounds of formula (I).

Another object of the invention refers to the use of such compounds ofgeneral formula I for the manufacture of a medicament for the treatmentor prophylaxis of sigma receptor mediated diseases or conditions,especially sigma-1 mediated diseases or conditions. Within the group ofdiseases or conditions mediated by the sigma receptor for which thecompounds of the invention are effective, diarrhoea, lipoproteindisorders, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia,obesity, migraine, arthritis, hypertension, arrhythmia, ulcer, glaucoma,learning, memory and attention deficits, cognition disorders,neurodegenerative diseases, demyelinating diseases, addiction to drugsand chemical substances including cocaine, amphetamine, ethanol andnicotine; tardive diskinesia, ischemic stroke, epilepsy, stroke, stress,cancer, psychotic conditions, in particular depression, anxiety orschizophrenia; inflammation or autoimmune diseases, may be cited.Compounds of the invention are very good anxiolytic andimmunosuppressant and are especially useful in the treatment andprofilaxis of pain, especially neuropathic pain, inflammatory pain orother pain conditions involving allodynia and/or hyperalgesia.

It is also an object of the invention pharmaceutical compositionscomprising one or more compounds of general formula (I) with at leastone pharmaceutically acceptable excipient. The pharmaceuticalcompositions in accordance with the invention can be adapted in order tobe administered by any route of administration, be it orally orparenterally, such as pulmonarily, nasally, rectally and/orintravenously. Therefore, the formulation in accordance with theinvention may be adapted for topical or systemic application,particularly for dermal, subcutaneous, intramuscular, intra-articular,intraperitoneal, pulmonary, buccal, sublingual, nasal, percutaneous,vaginal, oral or parenteral application.

DETAILED DESCRIPTION OF THE INVENTION

The invention first relates to compounds of general formula (I):

whereinR₁ and R₂ independently represent a hydrogen atom;a branched or unbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀;a substituted or unsubstituted cycloalkyl radical C₃₋₉; a branched orunbranched cycloalkyl-alkyl radical C₁₋₁₀ group in which either thealkyl group and/or the cycloalkyl group is optionally at leastmono-substituted; a substituted or unsubstituted cycloalkyl C₃₋₉ orcycloalkylalkyl C₁₋₁₀ group in which the cycloalkyl group is condensedwith another substituted or unsubstituted mono- or polycyclic ringsystem;a substituted or unsubstituted aryl radical; a substituted orunsubstituted, branched or unbranched arylalkyl radical C₁₋₁₀ or abenzhydryl group optionally monosubstituted;a substituted or unsubstituted heteroaryl radical; a substituted orunsubstituted, branched or unbranched heteroarylalkyl radical C₁₋₁₀; asubstituted or unsubstituted non-aromatic heterocyclyl radical C₃₋₉; asubstituted or unsubstituted, branched or unbranched heterocyclylalkylradical C₃₋₉;a substituted or unsubstituted heterocyclyl C₃₋₉ or heterocyclyl-alkylradical C₁₋₁₀ group in which the heterocyclyl group is condensed withanother substituted or unsubstituted mono- or polycyclic ring system;or R₁ and R₂ together with the bridging nitrogen form a substituted orunsubstituted cycloalkyl radical C₃₋₉; a substituted or unsubstitutedheterocyclyl group C₃₋₉ or a substituted or unsubstituted heteroarylradical C₃₋₉;R₃ and R₄ independently represent a hydrogen atom; a —COR₅; —C(O)NR₅R₆;—C(S)NR₅R₆; —SO₂R₇; —C(O)OR₅; —OR₅; —NR₅R₆; NR₅C(O)R₆; —NCR₅R₆;a branched or unbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀;a substituted or unsubstituted cycloalkyl radical C₃₋₉; a branched orunbranched cycloalkyl-alkyl radical C₁₋₁₀ group in which either thealkyl group and/or the cycloalkyl group is optionally at leastmono-substituted; a substituted or unsubstituted cycloalkyl C₃₋₉ orcycloalkyl-alkyl C₁₋₁₀ group in which the cycloalkyl group is condensedwith another substituted or unsubstituted mono- or polycyclic ringsystem;a substituted or unsubstituted aryl radical; a substituted orunsubstituted, branched or unbranched arylalkyl radical C₁₋₁₀ or abenzhydryl group optionally monosubstituted;a substituted or unsubstituted heteroaryl radical; a substituted orunsubstituted, branched or unbranched heteroarylalkyl radical C₁₋₁₀; asubstituted or unsubstituted non-aromatic heterocyclyl radical C₃₋₅; asubstituted or unsubstituted, branched or unbranched heterocyclylalkylradical C₃₋₅;a substituted or unsubstituted heterocyclyl C₃₋₅ or heterocyclyl-alkylradical C₁₋₁₀ group in which the heterocyclyl group is condensed withanother substituted or unsubstituted mono- or polycyclic ring system;or R₃ and R₄ together with the bridging nitrogen form a substituted orunsubstituted cycloalkyl radical C₃₋₅; a substituted or unsubstitutedheterocyclyl group C₃₋₅ or a substituted or unsubstituted heteroarylradical C₃₋₅;R₅, R₆ and R₇ independently represent a hydrogen atom;a branched or unbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀;a substituted or unsubstituted cycloalkyl radical C₃₋₅; a branched orunbranched cycloalkyl-alkyl radical C₁₋₁₀ group in which either thealkyl group and/or the cycloalkyl group is optionally at leastmono-substituted; a substituted or unsubstituted cycloalkyl C₃₋₅ orcycloalkyl-alkyl C₁₋₁₀ group in which the cycloalkyl group is condensedwith another substituted or unsubstituted mono- or polycyclic ringsystem;a substituted or unsubstituted aryl radical; a substituted orunsubstituted, branched or unbranched arylalkyl radical C₁₋₁₀ or abenzhydryl group optionally monosubstituted;a substituted or unsubstituted heteroaryl radical; a substituted orunsubstituted, branched or unbranched heteroarylalkyl radical C₁₋₁₀; asubstituted or unsubstituted non-aromatic heterocyclyl radical C₃₋₅; asubstituted or unsubstituted, branched or unbranched heterocyclyl-alkylradical C₁₋₁₀;a substituted or unsubstituted heterocyclyl C₃₋₅ or heterocyclyl-alkylradical C₁₋₁₀ group in which the heterocyclyl group is condensed withanother substituted or unsubstituted mono- or polycyclic ring system;n is selected from 1, 2, 3 or 4;or a pharmaceutically acceptable salt, isomer, prodrug or solvatethereof.

Aliphatic radicals C₁₋₁₀, as referred to in the present invention, areoptionally mono- or polysubstituted and may be branched or unbranched,saturated or unsaturated. Unsaturated aliphatic groups, as defined inthe present invention, include alkyl, alkenyl and alkinyl radicals.Preferred aliphatic radicals according to the present invention includebut are not restricted to methyl, ethyl, vinyl (ethenyl), ethinyl,propyl, n-propyl, isopropyl, allyl (2-propenyl), 1-propinyl,methylethyl, butyl, n-butyl, iso-butyl, sec-butyl, tert-butyl butenyl,butinyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,hexyl, 1-methylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Preferredsubstituents for aliphatic radicals, according to the present invention,are a C₁₋₄ alkyl group, a linear or branched C₁₋₆ alkoxy group, F, CI,I, Br, CF₃, CH₂F, CHF₂, CN, OH, SH, NH₂, oxo, (C═O)R′, SR′, SOR′, SO₂R′,NHR′, NR′R″ whereby R′ and optionally R″ for each substitutentindependently represents a linear or branched C₁₋₆-alkyl group.

Alkyl radicals, as referred to in the present invention, are saturatedaliphatic radicals. They may be linear or branched and are optionallysubstituted.

Cycloalkyl radical C₃₋₉, as referred to in the present invention, areunderstood as meaning saturated and unsaturated (but not aromatic),cyclic hydrocarbons, which can optionally be unsubstituted, mono- orpolysubstituted. In these radicals, for example C₃₋₄-cycloalkylrepresents C₃- or C₄-cycloalkyl, C₃₋₆-cycloalkyl represents C₃-, C₄- orC₅-cycloalkyl, etc. With respect to cycloalkyl, the term also includessaturated cycloalkyls in which optionally at least one carbon atom maybe replaced by a heteroatom, preferably S, N, P or O. However, mono- orpolyunsaturated, preferably monounsaturated, cycloalkyls without aheteroatom in the ring also in particular fall under the term cycloalkylas long as the cycloalkyl is not an aromatic system.

Examples for cycloalkyl radical preferably include but are notrestricted to cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl,cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl,cyclooctyl, acetyl, tert-butyl, adamantyl, noradamantyl, pyrroline,pyrrolidine, pyrrolidineone, pyrazoline, pyrazolinone, oxopyrazolinone,aziridine, azetidine, tetrahydropyrrole, oxirane, oxetane, dioxetane,tetrahydrofurane, dioxane, dioxolane, oxathiolane, oxazolidine,thiirane, thietane, thiolane, thiane, thiazolidine, piperidine,piperazine, morpholine or azepane.

Cycloalkyl radicals C₃₋₉, as defined in the present invention, areoptionally mono- or polysubstituted by substitutents independentlyselected from a C₁₋₄-alkyl group, a linear or branched C₁₋₆-alkoxygroup, a phenyl group, F, CI, I, Br, CF₃, CH₂F, CHF₂, CN, OH, SH, NH₂,oxo (═O), (C═O)R′, SR′, SOR′, SO₂R′, NHR′, NR′R″ whereby R′ andoptionally R″ for each substitutent independently represents a linear orbranched C₁₋₆-alkyl group.

An aryl radical, as referred to in the present invention, is understoodas meaning ring systems with at least one aromatic ring but withoutheteroatoms even in only one of the rings. These aryl radicals mayoptionally be mono- or polysubstituted by substitutents independentlyselected from a C₁₋₄ alkyl group, a linear or branched C₁₋₆ alkoxygroup, an optionally at least mono-substituted phenyl group, F, CI, I,Br, CF₃, CH₂F, CHF₂, CN, OH, SH, NH₂, oxo, (C═O)R′, SR′, SOR′, SO₂R′,N(C═O) OR′, NHR′, NR′R″ whereby R′ and optionally R″ for eachsubstitutent independently represents a linear or branched C₁₋₆-alkylgroup. Preferred examples of aryl radicals include but are notrestricted to phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl orindanyl or anthracenyl radicals, which may optionally be mono- orpolysubstituted, if not defined otherwise.

An arylalkyl radical C₁₋₁₀, as defined in the present invention,comprises a linear or branched, optionally at least mono-substitutedalkyl chain which is bonded to an aryl group, as defined above. Apreferred aryl-alkyl radical is a benzyl group, wherein the alkyl chainis optionally branched or substituted. Preferred substituents foraryl-alkyl radicals, according to the present invention, are F, CI, Br,I, NH₂, SH, OH, SO₂, CF₃, carboxy, amido, cyano, carbamyl, nitro,phenyl, benzyl, —SO₂NH₂, C₁₋₆ alkyl and/or C₁₋₆-alkoxy.

A heteroaryl radical C₃₋₉, is understood as meaning heterocyclic ringsystems which have at least one aromatic ring and may optionally containone or more heteroatoms from the group consisting of nitrogen, oxygenand/or sulfur and may optionally be mono- or polysubstituted bysubstitutents independently selected from a C₁₋₄-alkyl group, a linearor branched C₁₋₆ alkoxy group, F, CI, I, Br, CF₃, CH₂F, CHF₂, CN, OH,SH, NH₂, oxo, (C═O)R′, SR′, SOR′, SO₂R′, NHR′, NR′R″ whereby R′ andoptionally R″ for each substitutent independently represents a linear orbranched C₁₋₆-alkyl group. Preferred examples of heteroaryls include butare not restricted to furan, benzofuran, thiophene, benzothiophene,imidazole, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine,quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole,benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane,benzimidazole, carbazole and quinazoline.

The term “condensed” according to the present invention means that aring or ring-system is attached to another ring or ring-system, wherebythe terms “annulated” or “annelated” are also used by those skilled inthe art to designate this kind of attachment.

The term “ring system” according to the present invention refers to ringsystems comprises saturated, unsaturated or aromatic carbocyclic ringsystems which contain optionally at least one heteroatom as ring memberand which are optionally at least mono-substituted. Said ring systemsmay be condensed to other carbocyclic ring systems such as aryl groups,naphtyl groups, heteroaryl groups, cycloalkyl groups, etc.

Cyclyl groups/radicals C₃₋₉, as defined in the present invention,comprise any saturated, unsaturated or aromatic carbocyclic ring systemswhich contain optionally at least one heteroatom as ring member andwhich are optionally at least mono-substituted. Cyclyl groups preferablycomprise aryl, heteroaryl, cyclyl, heterocylcyl and/or spiro ringsystems.

Heterocyclyl groups/radicals C₃₋₉, as defined in the present invention,comprise any saturated, unsaturated or aromatic carbocyclic ring systemswhich are optionally at least mono-substituted and which contain atleast one heteroatom as ring member. Preferred heteroatoms for theseheterocyclyl groups are N, S or O. Preferred substituents forheterocyclyl radicals, according to the present invention, are F, CI,Br, I, NH₂, SH, OH, SO₂, CF₃, carboxy, amido, cyano, carbamyl, nitro,phenyl, benzyl, —SO₂NH₂, C₁₋₆ alkyl and/or C₁₋₆-alkoxy.

The term “salt” must be understood as any form of an active compoundused in accordance with this invention in which the said compound is inionic form or is charged and coupled to a counter-ion (a cation oranion) or is in solution. This definition also includes quaternaryammonium salts and complexes of the active molecule with other moleculesand ions, particularly complexes formed via ionic interactions. Thedefinition particularly includes physiologically acceptable salts; thisterm must be understood as equivalent to “pharmacologically acceptablesalts”.

The term “pharmaceutically acceptable salts” in the context of thisinvention means any salt that is tolerated physiologically (normallymeaning that it is not toxic, particularly as a result of thecounter-ion) when used in an appropriate manner for a treatment,particularly applied or used in humans and/or mammals. Thesephysiologically acceptable salts may be formed with cations or basesand, in the context of this invention, are understood to be salts formedby at least one compound used in accordance with the invention—normallyan acid (deprotonated)—such as an anion and at least one physiologicallytolerated cation, preferably inorganic, particularly when used on humansand/or mammals. Salts with alkali and alkali earth metals areparticularly preferred, as well as those formed with ammonium cations(NH₄ ⁺). Preferred salts are those formed with (mono) or (di)sodium,(mono) or (di)potassium, magnesium or calcium. These physiologicallyacceptable salts may also be formed with anions or acids and, in thecontext of this invention, are understood as being salts formed by atleast one compound used in accordance with the invention—normallyprotonated, for example in nitrogen—such as a cation and at least onephysiologically tolerated anion, particularly when used on humans and/ormammals. This definition specifically includes in the context of thisinvention a salt formed by a physiologically tolerated acid, i.e. saltsof a specific active compound with physiologically tolerated organic orinorganic acids—particularly when used on humans and/or mammals.Examples of this type of salts are those formed with: hydrochloric acid,hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid,acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid,mandelic acid, fumaric acid, lactic acid or citric acid.

The term “solvate” in accordance with this invention should beunderstood as meaning any form of the active compound in accordance withthe invention in which said compound is bonded by a non-covalent bond toanother molecule (normally a polar solvent), especially includinghydrates and alcoholates, for example methanolate.

In a particular and preferred embodiment of the invention R₁ and R₂independently represent a hydrogen atom; a branched or unbranched,saturated or unsaturated, optionally at least mono-substituted,aliphatic radical C₁₋₁₀; or R₁ and R₂ together with the bridgingnitrogen form a substituted or unsubstituted cycloalkyl radical C₃₋₉; asubstituted or unsubstituted heterocyclyl group C₃₋₉ or a substituted orunsubstituted heteroaryl radical C₃₋₉.

In another preferred embodiment of the invention R₃ and R₄ independentlyrepresent a hydrogen atom; or an —COR₅; —C(O)NR₅R₆; —C(S)NR₅R₆; —SO₂R₇;or a branched or unbranched, saturated or unsaturated, optionally atleast mono-substituted, aliphatic radical C₁₋₁₀; or R₃ and R₄ togetherwith the bridging nitrogen form a substituted or unsubstitutedcycloalkyl radical C₃₋₉; a substituted or unsubstituted heterocyclylgroup C₃₋₉ or a substituted or unsubstituted heteroaryl radical C₃₋₉;

In another preferred embodiment of the invention R₅, R₆ and R₇independently represent a hydrogen atom;

a branched or unbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀;a substituted or unsubstituted cycloalkyl radical C₃₋₉; a branched orunbranched cycloalkyl-alkyl radical C₁₋₁₀ group in which either thealkyl group and/or the cycloalkyl group is optionally at leastmono-substituted; a substituted or unsubstituted cycloalkyl C₃₋₉ orcycloalkyl-alkyl C₁₋₁₀ group in which the cycloalkyl group is condensedwith another substituted or unsubstituted mono- or polycyclic ringsystem;a substituted or unsubstituted aryl radical; a substituted orunsubstituted, branched or unbranched arylalkyl radical C₁₋₁₀ or atleast mono-substituted benzhydryl group;a substituted or unsubstituted heteroaryl radical; a substituted orunsubstituted, branched or unbranched heteroarylalkyl radical C₁₋₁₀; asubstituted or unsubstituted non-aromatic heterocyclyl radical C₃₋₉; asubstituted or unsubstituted, branched or unbranched heterocyclyl-alkylradical C₁₋₁₀;a substituted or unsubstituted heterocyclyl C₃₋₉ or heterocyclyl-alkylradical C₁₋₁₀ group in which the heterocyclyl group is condensed withanother substituted or unsubstituted mono- or polycyclic ring system.

In a more particular and preferred embodiment of the invention R₁ and R₂independently represent hydrogen atom; a branched or unbranched,saturated or unsaturated, optionally at least mono-substituted,aliphatic radical C₁₋₁₀; or where R₁ and R₂ together with the bridgingnitrogen form an optionally at least monosubstituted group selectedfrom:

where R_(a) independently represents a hydrogen, a branched orunbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀ or a (C═O)R′ group where R′represents a a linear or branched C₁₋₆-alkyl group.

In another more particular and preferred embodiment of the invention R₃and R₄ independently represent a hydrogen atom; or an —COR₅; —C(O)NR₅R₆;—C(S)NR₅R₆; —SO₂R₇; or a branched or unbranched, saturated orunsaturated, optionally at least mono-substituted, aliphatic radicalC₁₋₁₀; or R₃ and R₄ together with the bridging nitrogen form a groupselected from:

where R_(b) independently represents a hydrogen, a halogen atom, aphenyl group, a branched or unbranched, saturated or unsaturated,optionally at least mono-substituted, aliphatic radical C₁₋₁₀ or a(C═O)R′ group where R′ represents a a linear or branched C₁₋₆-alkylgroup; R′_(b) is a branched or unbranched, saturated or unsaturated,optionally at least mono-substituted, aliphatic radical C₁₋₁₀ and mrepresents 1, 2, 3 or 4.

Another more particular and preferred embodiment of the invention isillustrated when R₅, R₆ and R₇ independently represent a hydrogen atom;a branched or unbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀; or an optionally at leastmono-substituted group selected from:

where R_(c) independently represents a hydrogen, a halogen atom, an —OHor a branched or unbranched, saturated or unsaturated, optionally atleast mono-substituted, aliphatic radical C₁₋₁₀.

The more preferred embodiment of the invention is when R₁ and R₂independently represent hydrogen atom; a branched or unbranched,saturated or unsaturated, optionally at least mono-substituted,aliphatic radical C₁₋₁₀; or where R₁ and R₂ together with the bridgingnitrogen form an optionally at least mono-substituted group selectedfrom:

R_(a) independently representing a hydrogen, a branched or unbranched,saturated or unsaturated, optionally at least mono-substituted,aliphatic radical C₁₋₁₀ or a (C═O)R′ group where R′ represents a alinear or branched C₁₋₆-alkyl group;R₃ and R₄ independently represent a hydrogen atom; or an —COR₅;—C(O)NR₅R₆; —C(S)NR₅R₆ or —SO₂R₇; or R₃ and R₄ together with thebridging nitrogen form a group selected from:

where R_(b) independently represents a hydrogen, a halogen atom, aphenyl group, a branched or unbranched, saturated or unsaturated,optionally at least mono-substituted, aliphatic radical C₁₋₁₀ or a —NHR′group where R′ represents a a linear or branched C₁₋₆-alkyl group;R′_(b) is a branched or unbranched, saturated or unsaturated, optionallyat least mono-substituted, aliphatic radical C₁₋₁₀ and m represents 1,2, 3 or 4.R₅, R₆ and R₇ independently represent a hydrogen atom; a branched orunbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀; or an optionally at leastmono-substituted group selected from:

R_(c) independently representing a hydrogen, a halogen atom, an —OH or abranched or unbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀;and n is selected from 1, 2, 3 or 4.

The compounds of the present invention represented by the abovedescribed formula (I) may include enantiomers depending on the presenceof chiral centres or isomers depending on the presence of double bonds(e.g. Z, E). The single isomers, enantiomers or diastereoisomers andmixtures thereof fall within the scope of the present invention.

The compounds obtained according to the invention may, if desired, bepurified by conventional methods, such as crystallisation andchromatography. Where the preparation of compounds of the invention,give rise mixtures of stereoisomers, these isomers may be separated byconventional techniques such as preparative chromatography. If there arechiral centers the compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution.

One preferred pharmaceutically acceptable form is the crystalline form,including such form in pharmaceutical composition. In the case of saltsand solvates the additional ionic and solvent moieties must also benon-toxic. The compounds of the invention may present differentpolymorphic forms, it is intended that the invention encompasses allsuch forms.

Among all the compounds encompassed by the general formula (I) thefollowing compounds are particularly preferred:

-   N-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide    maleate-   N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-naphthamide-   2-fluoro-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide-   N-(1-[2-(Piperidin-1-yl)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-adamantyl    carboxamide maleate-   N-(1-(2-(Piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide    maleate-   N-(1-(2-(Piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane    carboxamide hydrochloride-   2,4-Dichloro-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide    hydrochloride-   1,5-dimethyl-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1H-pyrazole-3-carboxamide    hydrochloride-   3,5-di-tert-Butyl-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide    hydrochloride-   2-hydroxy-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide    hydrochloride-   N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(1-noradamantyl    carboxamide) maleate-   N-(1-(2-Morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide    hydrochloride-   N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide    hydrochloride-   N-(1-(2-Morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane    carboxamide hydrochloride-   N-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane    carboxamide maleate-   N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane    carboxamide maleate-   N-(1-[2-(Morpholinoethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-adamantyl    carboxamide hydrochloride-   N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-adamantyl    carboxamide maleate-   N-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)    1-adamantyl carboxamide hydrochloride-   N-(1-[2-(Morpholinoethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-noradamantyl    carboxamide hydrochloride-   N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-noradamantylcarboxamide    hydrochloride-   N-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)    1-noradamantyl carboxamide hydrochloride-   2,4-Dichloro-N-(1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide    hydrochloride-   N-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2,4-dichloro    benzamide hydrochloride-   2,4-Dichloro-N-(1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide    hydrochloride-   N-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide    hydrochloride-   N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide    hydrochloride-   N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclopentane    carboxamide maleate-   N-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclopentane    carboxamide maleate-   N-(1-(2-(4-isopropylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)    pivalamide maleate-   N-(1-(2-(4-isopropylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)    1-adamantylcarboxamide maleate-   N-(1-(2-(4-isopropylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclopentanecarboxamide    maleate-   4-fluoro-N-(1-(2-(4-isopropylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide    maleate-   N-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-fluorobenzamide    citrate-   N-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2,2,3,3-tetramethyl    cyclopropanecarboxamide citrate-   N-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4,4-difluoro    cyclohexanecarboxamide maleate-   N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclobutane    carboxamide maleate-   N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane    carboxamide maleate-   N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclopentane    carboxamide maleate-   N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclopropane    carboxamide maleate-   N-(1-(4-(azepan-1-yl)butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide    maleate-   N-(1-(3-(azepan-1-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide    maleate-   N-(1-(2-((3S,5R)-3,5-dimethylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide-   1-(1-(2-(1,4-oxazepan-4-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea-   1-tert-Butyl-3-(1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea    hydrochloride-   1-Cyclohexyl-3-(1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea    hydrochloride-   1-Adamanthyl-3-(1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea    hydrochloride-   1-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-ethylurea    hydrochloride-   1-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-cyclopentylurea    hydrochloride-   1-(2,4-Dichlorophenyl)-3-(1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea    hydrochloride-   1-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-cyclohexylurea    hydrochloride-   1-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-ethylurea    hydrochloride-   1-Cyclopentyl-3-(1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea    hydrochloride-   1-Cyclopentyl-3-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea    hydrochloride-   1-Ethyl-3-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea    hydrochloride-   1-Adamanthyl-3-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)    urea hydrochloride-   1-Cyclohexyl-3-(1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)    urea hydrochloride-   1-(2,4-Dichlorophenyl)-3-(1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea    hydrochloride-   1-Cyclohexyl-3-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea    hydrochloride-   1-(2,4-Dichlorophenyl)-3-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea    hydrochloride-   1-tert-Butyl-3-(1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)    urea hydrochloride-   1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-tert-butylurea    hydrochloride-   1-Adamanthyl-3-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea    maleate-   1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-(2,4-dichloro    phenyl)urea citrate-   1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-(2,4,4-trimethylpentan-2-yl)urea    maleate-   1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea    maleate-   1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-butylurea    hydrochloride-   1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-cyclopropylurea    hydrochloride-   1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-isopropylurea    hydrochloride-   1-isopropyl-3-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea    hydrochloride-   1-propyl-3-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea    hydrochloride-   1-(1-(4-(azepan-1-yl)butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea    maleate-   1-(1-(3-(azepan-1-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea-   1-(1-(2-(4-tert-butylpiperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea-   1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-butylthiourea    maleate-   1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylthiourea    maleate-   1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylthiourea-   1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-ethylthiourea-   1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-cyclopropyl    thiourea hydrochloride-   2,4-Dichloro-N-(1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzenesulfonamide    hydrochloride-   N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexane    sulfonamide hydrochloride-   N-(1-(2-(4-tert-butylpiperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide-   N-(1-(2-(1,4-oxazepan-4-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide-   N-(1-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide-   N-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide-   N-(1-(3-(4-methylpiperazin-1-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide-   N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide    maleate-   N-(1-(4-(4-tert-butylpiperidin-1-yl)butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide    maleate-   1-(1-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea-   1-(1-(3-(4-methylpiperazin-1-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea-   1-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea-   1-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea-   1-(1-(4-(4-tert-butylpiperidin-1-yl)butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea-   1-(1-(2-(4-acetylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea-   1-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea-   2,4-dichloro-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzenesulfonamide-   N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)methanesulfonamide-   N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)propane-2-sulfonamide-   N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexanesulfonamide-   N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ethanesulfonamide-   N-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylacetamide-   1-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyrrolidin-2-one-   4-(1H-imidazol-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine-   4-(1H-benzo[d]imidazol-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine-   4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine-   4-(4,4-difluoropiperidin-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine-   4-(3,3-dimethylpyrrolidin-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine-   4-(3-phenylpyrrolidin-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine-   N-methyl-1-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyrrolidin-3-amine-   4-(piperidin-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine

A specific embodiment of the invention is that in which thepyrazolo[3,4-d]pyrimidine compounds of the invention are defined by thefollowing general formula (Ia):

where R₁, R₂, R₄, R₅ and n have the same meanings as in formula (I).

Another specific embodiment is that in which pyrazolo[3,4-d]pyrimidinecompounds of the invention are defined by general formula (Ib)

where R₁, R₂, R₄, R₆ and n have the same meaning as in formula (I) and Zrepresents either S or O.

An additional, specific embodiment of the invention is provided wherepyrazolo[3,4-d]pyrimidine compounds of the invention are represented bygeneral formula (Ic):

where R₁, R₂, R₄, R₇ and n have the same meaning as in formula (I).

A further specific embodiment is that in which pyrazolo[3,4-d]pyrimidinecompounds of the invention are defined by general formula (Id):

where R₁, R₂ and n have the same meaning as for formula (I) and Hetrepresents with the N a substituted or unsubstituted cycloalkyl radicalC₃₋₉; a substituted or unsubstituted heterocyclyl group C₃₋₉ or asubstituted or unsubstituted heteroaryl radical C₃₋₉.

In a still more particular embodiment, compounds of general formula(Id′) are those compounds of general formula (Id) where Het particularlyrepresents a group selected from:

Similarly, in a more particular embodiment compounds of general formula(Id) are designated as compounds of formula (Id″) when Het areparticularly represented by the following group:

where R′_(b) is a branched or unbranched, saturated or unsaturated,optionally at least mono-substituted, aliphatic radical C₁₋₁₀.

A further specific embodiment is that in which pyrazolo[3,4-d]pyrimidinecompounds of the invention are defined by general formula (Ie):

where R₁, R₂ and n have the same meaning as for formula (I) and mrepresents 1, 2, 3 or 4.

In another aspect the invention refers to the processes for obtainingthe compounds of general formula (I). Several processes have beendeveloped for obtaining all the compounds of the invention. Thedifferent processes are explained as methods A to F.

Method A

A process is described for the preparation of a compound of generalformula (Ia):

comprising the reaction between a compound of general formula (IX):

with a compound of general formula (X):

wherein R₁, R₂, R₄, R₅ and n have the meanings as in general formula (I)and X is a halogen.

The reaction of compounds of formula (IX) and (X) is preferably carriedout at a temperature range of 90-125° C. in an aprotic solvent such astoluene or tetrahydrofuran in the presence of an organic base such aspyridine or DMAP. Alternatively the reaction can be carried out in amicrowave reactor.

Method B

The process for the synthesis of compounds of formula (Ib):

comprises the reaction between a compound of general formula (IX):

with a compound of general formula (XI):

R₆NCZ  (XI)

where R₁, R₂, R₆ and n have the meanings as in general formula (I) and Zrepresents O or S.

The reaction of compounds of formula (IX) and (XI) is preferably carriedout in an aprotic solvent such as toluene or acetonitrile at atemperature range of 50-120° C. Alternatively, the reaction can becarried out in a microwave reactor.

Method C

The method for the synthesis of compounds of general formula (Ic):

comprises the reaction between a compound of general formula (IX):

with a compound of general formula (XII):

R₇SO₂X  (XII)

where R₁, R₂, R₇ and n have the meanings as in general formula (I) and Xrepresents a halogen.

The reaction of compounds of formula (IX) and (XII) is preferablycarried out at a temperature range of 50-125° C. in an aprotic solventsuch as toluene or tetrahydrofuran in the presence of an organic basesuch as pyridine or DMAP. Alternatively, the reaction can be carried outin a microwave reactor.

Method D

The process for the synthesis of compounds of formula (Id):

comprises de reaction between a compound of general formula (XIV):

with an heterocyclic compound of formula (XVI):

where R₁, R₂, and n have the meanings as in general formula (I) and X isa halogen.

The reaction of compounds of formula (XIV) and heterocycles (XVI) ispreferably carried out at a temperature range of 0° C. and the boilingpoint of an aprotic solvent such as THF, DMF or pyridine in the presenceof a base such as sodium hydride or potassium tert-butoxide. Theseconditions are specially suited for preparing compounds of generalformula (Id′) as defined above, that is for compounds where Hetrepresents an imidazole-like compound.

Compounds of formula (Id″):

can be prepared by reaction of a compound of formula (VII):

with a 1,4-dione of formula (XIX):

where R₁, R₂ and n has the same meanings as for formula (I) and R′_(b)is a branched or unbranched, saturated or unsaturated, optionally atleast mono-substituted, aliphatic radical C₁₋₁₀.

The reaction of compounds of formula (VII) and 1,4-diones (XIX) arepreferably carried out without a solvent or in presence of an acid suchas acetic acid at a temperature of 140-160° C. Alternatively, thereaction can be carried out in a microwave reactor.

Method E

The process for the synthesis of compounds of formula (I):

comprising the reaction between a compound of general formula (XIV):

with amines of formula R₃R₄NH (XVIII)

where R₁, R₂ R₃, R₄, and n have the meanings as in general formula (I)and X is a halogen.

The reaction of compounds of formula (XIV) and amines (XVIII) ispreferably carried out at a temperature range of 0° C. and the boilingpoint of a solvent such as methanol, ethanol, THF, DMF.

Method F

The process for the synthesis of compounds of formula (Ie):

comprises de reaction between a compound of general formula (XIV):

with a compound of formula general (XVII)

where R₁, R₂, and n have the meanings as in general formula (I) and m isselected from 1, 2, 3 or 4 and X is a halogen.

The reaction of compounds of formula (XIV) and (XVII) is preferablycarried out under catalytic conditions, with catalysis such as palladiumdiacetate, tris(dibenzylideneacetone)dipalladium(0) ortris(dibenzylideneacetone)dipalladium(0) chloroform complex in thepresence of ligands such as xantphos, in the presence of base such ascaesium carbonate or potassium phosphate and in solvents such as tolueneo 1,4-dioxane at a temperature range of 50° C. and the boiling point ofthe solvent or in a microwave reactor.

A general synthetic route describing methods A to C is shown in thefollowing scheme 1:

compound (VII) corresponds to specific embodiment of general formula (I)wherein R₃ and R₄ are H.

As observed in scheme 1 all three methods A to C are carried out byreaction of the same starting material, namely compound (IX). Compound(IX) can be obtained by reductive amination of a compound of formula(VII) with an aldehyde (VIII). The type of aldehyde to be used willdepend on the meaning of the final substituent R₄. For instance, if R₄is intended to represent a methyl group formaldehyde should be used, ifan ethyl group is desired in position R₄ acetaldehyde should be usedetc.

Compounds of formula (VII) can be prepared by two different processes.In a first process they are prepared by reaction between compounds offormula (II) with a compound of formula (III) where Y is a suitableleaving group such as a halogen or a hydroxyl group. When Y is a halogenthe reaction is preferably carried out in an aprotic solvent such asdimethylformamide (DMF) in the presence of an inorganic base such asNaH. When Y is a hydroxyl group the reaction is performed underMitsunobu conditions.

A second process for the preparation of compounds of formula (VII)comprises the reaction between a compound of formula (V) where Y is asuitable leaving group such as a halogen, with an amine of formula (VI).The reaction between compounds of formula (V) and (VI) is preferablycarried out in an aprotic solvent such as dimethylformamide (DMF) in thepresence of an inorganic base, preferably K₂CO₃. An activating agent asNal can be used.

All compounds (II), (Ill) and (VI) are commercially available.Alternatively compound of formula (II) can be obtained by methodsdescribed in bibliography [WO2007126841; R. K. Robins, J. Am. Chem. Soc.784-790 (1956); S. Grupta et al., Eur. J. Med. Chem., 771-780 (2008)]and compounds of formula (III) and (VI) can be obtained by conventionalmethods. In turn, compounds of general formula (V) can be prepared bythe reaction of compounds II with compounds of formula (IV) where X andY are suitable different leaving groups. The reaction of compounds offormula (II) and (IV) is preferably carried out in an aprotic solvent,but no limited to, such as dimethylformamide (DMF) in the presence of aninorganic base, such as NaH.

Alternatively, the starting material of methods A, B and C, namelycompound (IX) can be obtained through the reaction of a compound ofgeneral formula (XIV) with a compound of formula (XV). This reaction ispreferably carried out in an aprotic solvent such as DMF or in a proticsolvent such as ethanol at a temperature range from 0° C. to solventboiling point. Compounds of formula (XIV) can be prepared by reactionbetween compounds of formula (XIII) with a compound of formula (III)where Y is a suitable leaving group such as a halogen. This reaction ispreferably carried out in an aprotic solvent such as dimethylformamide(DMF) in the presence of an inorganic base such as NaH. Compounds offormula (XIII) are commercially available.

Compounds of general formula (Ia), (Ib) and (Ic) where R₄ is Hydrogen[referred under the scheme below as (Ia), (Ib′) and (Ic′)] can beprepared by the direct reaction of intermediate (VII) with compounds(X), (XI) and (XII) respectively. The synthetic routes for thepreparation of compounds (Ia), (Ib′) and (Ic′) where R₄ is Hydrogen isrepresented in the following scheme 2:

The reaction of compounds of formula (VII) and (X) is preferably carriedout at a temperature range of 90-125° C. in an aprotic solvent such astoluene of tetrahydrofuran in the presence of an organic base such aspyridine or DMAP. Alternatively the reaction can be carried out in amicrowave reactor.

Compounds of formula (Ib′) can be prepared by reaction of a compound offormula (VII) with a compound of formula (XI) in which R₆ is as definedabove. Compounds of formula (XI) are commercially available.

The reaction of compounds of formula (VII) and (XI) is preferablycarried out in an aprotic solvent such as toluene or acetonitrile at atemperature range of 50-120° C. Alternatively, the reaction can becarried out in a microwave reactor.

Compounds of formula (Ic′) can be prepared by reaction of a compound offormula (VII) with a compound of formula (XII) in which R₇ is as definedabove. Compounds of formula (XII) are commercially available.

The reaction of compounds of formula (VII) and (XII) is preferablycarried out at a temperature range of 50-125° C. in an aprotic solventsuch as toluene of tetrahydrofuran in the presence of an organic basesuch as pyridine or DMAP. Alternatively, the reaction can be carried outin a microwave reactor.

The synthetic routes for the preparation of compounds (Id′), (I) and(Ie) according to methods D, E and F are depicted in the followingscheme 3:

As observed in scheme 3 all three methods D to F are carried out byreaction of the same starting material, namely compound (XIV). Compound(XIV) can be prepared by reaction between compounds of formula (XIII)with a compound of formula (III) where Y is a suitable leaving groupsuch as a halogen. This reaction is preferably carried out in an aproticsolvent such as dimethylformamide (DMF) in the presence of an inorganicbase such as NaH. Compounds of formula (XIII) are commerciallyavailable.

Finally, the synthetic route for the preparation of compounds (Id″),that is, compounds of formula (I) where R₃ together with R₄ formpyrrolic type moieties according to method F is depicted in thefollowing scheme 4:

R′b as expressed before independently represents a branched orunbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀.

An additional aspect of the invention relates to the therapeutic use ofthe compounds of general formula (I). As mentioned above, compounds ofgeneral formula (I) show a strong affinity to sigma receptors and canbehave as agonists, antagonists, inverse agonists, partial antagonistsor partial agonists thereof. For this reason, they are suitable for thetreatment and the prophylaxis of disorders and diseases mediated by thesigma receptors, especially, sigma-1 receptor. In this sense, compoundsof formula (I) are very good anxiolitic and immunosuppressant and arevery useful in the treatment and prophylaxis of diarrhoea, lipoproteindisorders, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia,obesity, migraine, arthritis, hypertension, arrhythmia, ulcer, glaucoma,learning, memory and attention deficits, cognition disorders,neurodegenerative diseases, demyelinating diseases, addiction to drugsand chemical substances including cocaine, amphetamine, ethanol andnicotine; tardive diskinesia, ischemic stroke, epilepsy, stroke, stress,cancer, psychotic conditions, in particular depression, anxiety orschizophrenia; inflammation or autoimmune diseases. The compounds offormula (I) are especially suited for the treatment of pain, especiallyneuropathic pain, inflammatory pain or other pain conditions involvingallodynia and/or hyperalgesia. PAIN is defined by the InternationalAssociation for the Study of Pain (IASP) as “an unpleasant sensory andemotional experience associated with actual or potential tissue damage,or described in terms of such damage (IASP, Classification of chronicpain, 2nd Edition, IASP Press (2002), 210). Even though pain is alwayssubjective its causes or syndromes can be classified.

Another aspect of the invention is a pharmaceutical composition whichcomprises a compound of general formula I or a pharmaceuticallyacceptable salt, prodrug, isomer or solvate thereof, and at least apharmaceutically acceptable carrier, additive, adjuvant or vehicle.

The auxiliary materials or additives can be selected among carriers,excipients, support materials, lubricants, fillers, solvents, diluents,colorants, flavour conditioners such as sugars, antioxidants and/oragglutinants. In the case of suppositories, this may imply waxes orfatty acid esters or preservatives, emulsifiers and/or carriers forparenteral application. The selection of these auxiliary materialsand/or additives and the amounts to be used will depend on the form ofapplication of the pharmaceutical composition.

The pharmaceutical composition in accordance with the invention can beadapted to any form of administration, be it orally or parenterally, forexample pulmonarily, nasally, rectally and/or intravenously. Therefore,the formulation in accordance with the invention may be adapted fortopical or systemic application, particularly for dermal, subcutaneous,intramuscular, intra-articular, intraperitoneal, pulmonary, buccal,sublingual, nasal, percutaneous, vaginal, oral or parenteralapplication.

Suitable preparations for oral applications are pills, chewing gums,capsules, granules, drops or syrups.

Suitable preparations for parenteral applications are solutions,suspensions, reconstitutable dry preparations or sprays.

The compounds of the invention as deposits in dissolved form or inpatches, for percutaneous application.

Skin applications include ointments, gels, creams, lotions, suspensionsor emulsions.

The preferred form of rectal application is by means of suppositories.

The amount of active ingredient that must be administered to the patientdepends on the patient's weight, the type of application, the conditionand severity of the disease. Normally, in human beings 1 to 500 mg ofthe active compound is administered daily in one or several doses.

Described below are a number of examples by way of illustration of theinvention and do not limit it in anyway.

Examples of Preparation of an Intermediate of Formula (VII) a) Synthesisof 1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

NaH (60% in mineral oil, 0.547 g, 16.3 mmol) was added over a solutionof 4-amino-1H-pyrazolo[3,4-d]pyrimidine (II) (2.0 g, 15.0 mmol) inanhydrous DMF (40 ml). The mixture was stirred at rt for 1 h, and then asolution in anhydrous DMF (2 ml) of 1-(2-chloroethyl)azepane was added(2.39 g, 15.0 mmol) dropwise. The mixture was stirred at rt for 18 h,allowed to cool to rt and poured into an NaHCO₃ aq. solution. Diethylether was added and the organic phase was separated. The aqueous phasewas extracted with diethyl ether, and the combined organic phases weredried over anh. Na₂SO₄, filtered and concentrated to dryness. Theresidue was poured into hexane and filtered to yield 1.13 g of1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. ¹H-NMR(DMSO-d₆) δ ppm: 8.15 (s, 1H), 8.05 (s, 1H), 7.6 (bs, 2H), 4.3 (t, J=6.7Hz, 2H), 2.9 (t, J=6.7 Hz, 2H), 2.55 (m, 4H), 1.4 (m, 8H).

b) Synthesis of1-(2-(4-tert-butylpiperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

4-amino-1H-pyrazolo[3,4-d]pyrimidine (II) (1.5 g, 0.011 mol) was addedin portions to a suspension of NaH (60% in mineral oil, 0.41 g, 0.012mol) in 20 ml of anhydrous DMF. After stirring for 2 h at rt, a solutionof 1-bromo-2-chlorobutane (1.06 ml, 0.013 mol) in 4 ml of anhydrous DMFwas added dropwise. The reaction was stirred at rt for 18 h., cooled at0° C. and quenched with water. The mixture was concentrated in vacuum,treated with EtOAc and filtered; the solution was concentrated and thecrude purified by flash chromatography (gradient from 100% EtOAc toEtOAc/MeOH 9:1) to yield 1.02 g of1-(2-chloroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid.

1-(2-chloroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.250 g, 0.001mol), 4-tert-butylpiperidine hydrochloride (0.405 g, 0.002 mol), K₂CO₃(0.524 g, 0.004 mol) and a catalytic amount of Nal were stirred in asolution of 10 ml of anhydrous DMF for 16 h at 95° C. Mixture wasconcentrated under reduced pressure, treated with EtOAc and filtered.The solution was evaporated to dryness and the residue treated withpetroleum ether and decanted to yield 0.225 g of a white solid.

Examples of Preparation of Compounds of General Formula (I) Example 1Synthesis ofN-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamidemaleate

1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.300 g,1.152 mmol), pivaloyl chloride (0.278 g, 2.30 mmol) in 3 mL of anhydrouspyridine with catalytic DMAP were heated in CEM microwave reactor for 15minutes at 130° C. The mixture was concentrated under reduced pressureand partitioned in EtOAc and 10% aq. NaOH sol. The organic layers werewashed with water, dried and evaporated to dryness. To an ice-cooledstirred solution in 2.5 mL of MeOH, 0.145 g (1.25 mmol) of maleic acidin 1 ml of MeOH was added dropwise. After stirring for 15 minutes at rt,the solvent was removed under vacuum and the residue washed with diethylether to obtain 450 mg ofN-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamidemaleate. ¹H NMR (CD₃OD) δ ppm: 8.67 (s, 1H), 8.63 (s, 1H), 6.25 (s, 2H),4.89 (t, J=5.8 Hz, 2H), 3.80 (t, J=5.9 Hz, 2H), 3.65-3.38 (m, 4H),2.04-1.86 (m, 4H), 1.81-1.65 (m, 4H), 1.38 (s, 9H).

Examples (2-43) were prepared following the same method as in example 1:

Ex. Structure Name NMR 2

N-(1-(2-(piperidin-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-1-naphthamide ¹H NMR (CDCl₃) δ ppm: 8.87 (s, 1H), 8.58 (s, 1H), 8.48 (d, J= 8.2 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.91(d, J = 7.8 Hz, 1H), 7.68-7.52 (m, 3H), 4.65 (t, J = 7.1 Hz, 2H), 2.91(t, J = 7.1 Hz, 2H), 2.56-2.46 (m, 4H), 1.57-1.48 (m, 4H), 1.47-1.33 (m,2H). 3

2-fluoro-N-(1-(2-(piperidin- 1-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)benzamide ¹H NMR (CD₃OD) δ ppm: 8.77 (s, 2H), 7.93 (td, J = 7.5, 1.8Hz, 1H), 7.79-7.64 (m, 1H), 7.51-7.28 (m, 2H), 4.97 (t, J = 5.9 Hz, 2H),3.77 (t, J = 5.9 Hz, 2H), 3.78-3.70 (m, 2H), 2.10-1.92 (m, 2H),1.92-1.67 (m, 3H), 1.67-1.46 (m, 1H). 4

N-(1-[2-(Piperidin-1- yl)ethyl]-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-1-adamantylcarboxamide maleate ¹H NMR (DMSO-d₆) δ ppm: 10.65 (s, 1H), 8.7(s, 1H), 8.45 (s, 1H), 6.0 (s, 2H), 4.75 (m, 2H), 3,6 (m, 4H), 2.95 (m,2H), 2.0 (m, 10H), 1.7-1.4 (m, 11H). 5

N-(1-(2-(Piperidin-1- yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide maleate ¹H NMR (DMSO-d₆) δ ppm: 10.75 (s,1H), 8.7 (s, 1H), 8.45 (s, 1H), 6.0 (s, 2H), 4.8 (m, 2H), 3.55 (m, 4H),3.0 (m, 2H), 1.8-1.5 (m, 6H), 1.3 (s, 9H). 6

N-(1-(2-(Piperidin-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)cyclohexanecarboxamide hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.75 (2 s,2H), 4.95 (t, J = 6.0 Hz, 2H), 3.75 (m, 4H), 3.05 (t, 2H), 2.65 (m, 1H),2.0- 1.75 (m, 10H), 1.6-1.3 (m, 6H). 7

2,4-Dichloro-N-(1-(2- (piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4- yl)benzamide hydrochloride ¹H NMR (CD₃OD) δppm: 8.75 (s, 1H), 8.7 (s, 1H), 7.7 (m, 2H), 7.55 (dd, J = 1.9 Hz; 8.4Hz, 1H), 4.95 (t, J = 6.0 Hz, 2H), 3.75 (m, 4H), 3.05 (t, J = 10.2 Hz,2H), 2.0-1.45 (m, 6H). 8

1,5-dimethyl-N-(1-(2- (piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-1H-pyrazole-3- carboxamide hydrochloride¹H NMR (CD₃OD) δ ppm: 8.88 (s, 1H), 8.77 (s, 1H), 6.78 (s, 1H), 4.97 (t,J = 5.9 Hz, 2H), 3.95 (s, 3H), 3.77 (t, J = 5.9 Hz, 2H), 3.77-3.67 (m,2H), 3.15-2.95 (m, 2H), 2.39 (s, 3H), 2.05- 1.90 (m, 2H), 1.90- 1.68 (m,3H), 1.66- 1.47 (m, 1H). 9

3,5-di-tert-Butyl-N-(1-(2- (piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4- yl)benzamide hydrochloride ¹H NMR (DMSO-d₆)δ ppm: 8.75 (bs, 1H), 8.55 (s, 1H), 8.5 (s, 1H), 7.95 (s, 2H), 7.7 (s,1H), 4.9 (t, J = 6.6 Hz, 2H), 3.6 (m, 4H), 2.95 (m, 2H), 1.8 (m, 6H),1.35 (s, 18H). 10

2-hydroxy-N-(1-(2- (piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4- yl)benzamide hydrochloride ¹H NMR (DMSO-d₆)δ ppm: 8.75 (s, 1H), 8.74 (s, 1H), 8.08 (dd, J = 7.9, 1.7 Hz, 1H), 7.59-7.46 (m, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.89(t, J = 6.4 Hz, 2H), 3.74- 3.54 (m, 4H), 3.06- 2.87 (m, 2H), 1.94- 1.56(m, 5H), 1.47- 1.27 (m, 1H). 11

N-(1-(2-(piperidin-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)(1-noradamantylcarboxamide) maleate ¹H NMR (DMSO-d₆) δ ppm: 10.53 (s, 1H),8.73 (s, 1H), 8.50 (s, 1H), 6.05 (s, 2H), 4.82 (t, J = 6.2 Hz, 2H), 3.60(t, J = 6.1 Hz, 2H), 3.28- 3.10 (m, 4H), 2.85 (t, J = 6.7 Hz, 1H), 2.41-2.25 (m, 2H), 2.25- 2.07 (m, 2H), 2.07- 1.95 (m, 2H), 1.95- 1.80 (m,2H), 1.80- 1.41 (m, 10H). 12

N-(1-(2-Morpholinoethyl)- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)pivalamidehydrochloride ¹H NMR (CD₃OD) δ ppm: 8.78 (s, 1H), 8.76 (s, 1H), 4.98 (t,J = 5.8 Hz, 2H), 4.17-4.00 (m, 2H), 3.84 (t, J = 5.8 Hz, 2H), 3.84-3.64(m, 4H), 3.30-3.23 (m, 2H), 1.41 (s, 9H). 13

N-(1-(2- (Diisopropylamino)ethyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.75 (s,2H), 4.9 (t, J = 7.0 Hz, 2H), 3.9 (m, 2H), 3.75 (t, J = 7.0 Hz, 2H),1.45 (d, J = 6.4 Hz, 12H), 1.4 (s, 9H). 14

N-(1-(2-Morpholinoethyl)- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)cyclohexanecarboxamide hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.75 (s,1H), 8.7 (s, 1H), 5.0 (t, J = 6.0 Hz, 4H), 4.05 (m, 2H), 3.85 (t, J =6.0 Hz, 4H), 3.7 (m, 2H), 2.7 (m, 1H), 2.0 (m, 2H), 1.9 (m, 2H), 1.8 (m,1H), 1.6-1.35 (m, 5H). 15

N-(1-(2-(Azepan-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)cyclohexanecarboxamide maleate ¹H NMR (DMSO-d₆) δ ppm: 11.23 (s, 1H),8.69 (s, 1H), 8.55 (s, 1H), 6.22-5.96 (m, 2H), 4.94-4.61 (m, 2H),3.79-3.51 (m, 4H), 2.68 (t, J = 11.2 Hz, 1H), 2.03-1.16 (m, 18H). 16

N-(1-(2- (Diisopropylamino)ethyl)- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)cyclohexanecarboxamide maleate ¹H NMR (CDCl₃) δ ppm: 8.7 (s, 1H), 8.6(s, 1H), 8.3 (bs, 1H), 6.3 (s, 2H), 5.0 (m, 2H), 3.8 (m, 2H), 3.4 (m,2H), 2.4 (m, 1H), 2.05 (m, 2H), 1.85 (m, 2H),1.75 (m, 2H), 1.6 (d, J =6.5 Hz, 12H), 1.45-1.2 (m, 4H). 17

N-(1-[2-(Morpholinoethyl]- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)-1-adamantylcarboxamide hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.8 (s, 1H),8.75 (s, 1H), 5.0 (t, J = 5.8 Hz, 2H), 4.1 (m, 2H), 3.85-3.65 (m, 8H),2.1 (m, 9H), 1.85 (m, 6H). 18

N-(1-(2- (Diisopropylamino)ethyl)- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)-1-adamantylcarboxamide maleate ¹H NMR (CDCl₃) δ ppm: 8.75 (s, 1H), 8.6 (s,1H), 8.4 (bs, 1H), 6.3 (s, 2H), 4.95 (m, 2H), 3.8 (m, 2H), 2.15 (m, 3H),2.05 (m, 6H), 1.8 (m, 8H), 1.5 (d, J = 6.6 Hz, 12H). 19

N-(1-(2-(Azepan-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl) 1-adamantylcarboxamide hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.79 (s, 1H),8.75 (s, 1H), 4.95 (t, J = 6.0 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H),3.69-3.57 (m, 2H), 3.40-3.31 (m, 2H), 2.19-2.07 (m, 8H), 2.04-1.81 (m,11H), 1.81-1.64 (m, 4H). 20

N-(1-[2-(Morpholinoethyl]- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)-1-noradamantylcarboxamide hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.8 (s, 1H),8.75 (s, 1H), 4.95 (t, J = 5.8 Hz, 2H), 4.1 (m, 2H), 3.85-3.65 (m, 6H),2.95 (m, 1H), 2.4 (m, 2H), 2.15 (m, 4H), 1.95 (m, 2H), 1.75 (m, 4H). 21

N-(1-(2- (Diisopropylamino)ethyl)- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)-1-noradamantylcarboxamide hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.75 (s,2H), 4.9 (t, J = 7.2 Hz, 2H), 3.9 (m, 2H), 3.75 (t, J = 7.2 Hz, 2H),2.95 (m, 1H), 2.4 (m, 2H), 2.15 (m, 3H), 1.95 (m, 2H), 1.75 (m, 3H),1.45 (d, J = 6.5 Hz, 12H). 22

N-(1-(2-(Azepan-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl) 1-noradamantylcarboxamide hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.75 (s,1H), 8.6 (s, 1H), 6.2 (s, 2H), 4.9 (m, 2H), 3.8 (t, J = 5.9 Hz, 2H), 2.9(t, J = 6.7 Hz, 1H), 2.45 (m, 2H), 2.15 (m, 4H), 1.75-1.65 (m, 18H). 23

2,4-Dichloro-N-(1-(2- (diisopropylamino)ethyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.75 (s,2H), 7.7 (s + d, J = 9.8 Hz, 2H), 7.5 (d, J = 8.4 Hz, 1H), 4.9 (t, J =7.1 Hz, 2H), 3.95 (m, 2H), 3.75 (t, J = 7.2 Hz, 2H), 1.45 (d, J = 6.5Hz, 12H). 24

N-(1-(2-(Azepan-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-2,4-dichlorobenzamide hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.75 (s, 2H), 7.70(d, J = 8.4 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.3, 2.0Hz, 1H), 4.95 (t, J = 5.9 Hz, 2H), 3.84 (t, J = 5.9 Hz, 2H), 3.71-3.57(m, 2H), 3.41-3.31 (m, 2H), 2.09-1.82 (m, 4H), 1.82-1.70 (m, 4H). 25

2,4-Dichloro-N-(1-(2- morpholinoethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)benzamide hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.75 (s, 2H), 7.7 (s +d, J = 11.2 Hz, 2H), 7.55 (dd, J = 8.3 Hz, 2.0 Hz, 1H), 4.95 (t, J = 5.8Hz, 2H), 4.1 (m, 2H), 3.85 (t, J = 5.8 Hz, 2H), 3.75-3.6 (m, 6H). 26

N-(1-(2-(Azepan-1- yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)tetrahydro- 2H-pyran-4-carboxamide hydrochloride ¹H NMR(CD₃OD) δ ppm: 8.76 (s, 1H), 8.73 (s, 1H), 4.94 (t, J = 5.9 Hz, 2H),4.03 (dt, J = 6.7, 3.6 Hz, 2H), 3.83 (t, J = 5.9 Hz, 2H), 3.76- 3.43 (m,4H), 3.36- 3.33 (m, 2H), 3.09- 2.86 (m, 1H), 2.04- 1.81 (m, 8H), 1.81-1.66 (m, 4H). 27

N-(1-(2- (Diisopropylamino)ethyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl)tetrahydro- 2H-pyran-4-carboxamide hydrochloride ¹H NMR(CD₃OD) δ ppm: 8.69, 8.68 (s, 1H), 8.44, 8.44 (s, 1H), 4.94- 4.80 (m,2H), 4.02 (dt, J = 11.3, 3.3 Hz, 1H), 3.97-3.81 (m, 3H), 3.73 (t, J =7.1 Hz, 2H), 3.59-3.38 (m, 2H), 2.98-2.77, 2.61-2.42 (m, 1H), 1.97-1.78(m, 3H), 1.78-1.57 (m, 1H), 1.54-1.34 (m, 12H). 28

N-(1-(2- (Diisopropylamino)ethyl)- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)cyclopentanecarboxamide maleate ¹H NMR (CDCl₃) δ ppm: 8.75 (s, 1H),8.6 (s, 1H), 6.3 (s, 2H), 4.95 (m, 2H), 3.8 (m, 2H), 3.45 (m, 2H), 2.9(m, 1H), 2.0 (m, 4H), 1.8 (m, 2H), 1.7 (m, 2H), 1.5 (bs, 12H). 29

N-(1-(2-(azepan-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)cyclopentanecarboxamide maleate ¹H NMR (DMSO-d₆) δ ppm: 11.31 (s,1H), 8.70 (s, 1H), 8.57 (s, 1H), 6.05 (s, 2H), 4.80 (t, J = 5.9 Hz, 2H),3.67 (t, J = 5.9 Hz, 2H), 3.26- 2.99 (m, 4H), 2.06- 1.41 (m, 17H). 30

N-(1-(2-(4- isopropylpiperazin-1- yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide maleate ¹H NMR (CD₃OD) δ ppm: 8.61 (s, 1H),8.54 (s, 1H), 6.25 (s, 2H), 4.62 (t, J = 6.0 Hz, 2H), 3.49-3.34 (m, 1H),3.48-2.31 (m, 8H), 3.01 (t, J = 6.0 Hz, 2H), 1.38 (s, 9H), 1.29 (d, J =6.6 Hz, 6H). 31

N-(1-(2-(4- isopropylpiperazin-1- yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl) 1- adamantylcarboxamide maleate ¹H NMR (CD₃OD) δ ppm:8.61 (s, 1H), 8.54 (s, 1H), 6.29 (s, 4H), 4.62 (t, J = 6.0 Hz, 2H),3.49-3.35 (m, 1H), 3.46-2.35 (m, 8H), 3.01 (t, J = 6.0 Hz, 3H),2.18-2.04 (m, 9H), 1.93-1.77 (m, 6H), 1.30 (d, J = 6.7 Hz, 6H). 32

N-(1-(2-(4- isopropylpiperazin-1- yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4- yl)cyclopentanecarboxamide maleate ¹H NMR (CD₃OD) δ ppm:8.59 (s, 1H), 8.57 (s, 1H), 6.28 (s, 4H), 4.61 (t, J = 6.0 Hz, 2H),3.48-3.35 (m, 1H), 3.55-2.28 (m, 8H), 3.12-2.97 (m, 1H), 3.01 (t, J =6.0 Hz, 2H), 2.11-1.55 (m, 8H), 1.30 (d, J = 6.6 Hz, 6H). 33

4-fluoro-N-(1-(2-(4- isopropylpiperazin-1- yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide maleate ¹H NMR (CD₃OD) δ ppm: 8.67 (s, 1H),8.59 (s, 1H), 8.14 (dd, J = 8.8, 5.3 Hz, 2H), 7.31 (t, J = 8.8 Hz, 2H),6.29 (s, 4H), 4.65 (t, J = 6.0 Hz, 2H), 3.51-3.38 (m, 1H), 3.57-2.26 (m,8H), 3.03 (t, J = 6.0 Hz, 2H), 1.31 (d, J = 6.6 Hz, 6H). 34

N-(1-(2-(azepan-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-4-fluorobenzamide citrate ¹H NMR (CD₃OD) δ ppm: 8.72 (s, 1H), 8.67 (s,1H), 8.14 (dd, J = 9.0, 5.3 Hz, 2H), 7.31 (dd, J = 9.0, 8.6 Hz, 2H),4.88 (t, J = 6.0 Hz, 2H), 3.72 (t, J = 6.0 Hz, 2H), 3.43-3.34 (m, 4H),2.78 (dd, J = 33.0, 14.6 Hz, 4H), 1.96- 1.85 (m, 4H), 1.77- 1.68 (m,4H). 35

N-(1-(2-(azepan-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-2,2,3,3-tetramethylcyclopropane- carboxamide citrate ¹H NMR (CD₃OD) δ ppm: 8.63(s, 1H), 8.61 (s, 1H), 4.85 (t, J = 5.6 Hz, 2H), 3.74 (t, J = 5.6 Hz,2H), 3.46-3.37 (m, 4H), 2.79 (dd, J = 28.6, 15.5 Hz, 4H), 1.97- 1.85 (m,4H), 1.80- 1.67 (m, 4H), 1.55 (s, 1H), 1.36 (s, 6H), 1.29 (s, 6H). 36

N-(1-(2-(azepan-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-4,4-difluorocyclohexanecarbox- amide maleate ¹H NMR (CD₃OD) δ ppm: 8.67 (s,1H), 8.66 (s, 1H), 6.26 (s, 2H), 4.88 (t, J = 5.9 Hz, 2H), 3.80 (t, J =5.9 Hz, 2H), 3.70-3.15 (m, 4H), 2.80-2.66 (m, 1H), 2.27-2.11 (m, 2H),2.11-1.82 (m, 10H), 1.81-1.68 (m, 4H). 37

N-(1-(2-(pyrrolidin-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)cyclobutanecarboxamide maleate ¹H NMR (CD₃OD) δ ppm: 8.72 (s, 1H),8.64 (s, 1H), 6.25 (s, 2H), 4.85 (t, J = 5.7 Hz, 2H), 3.84 (t, J = 5.7Hz, 2H), 3.61-3.40 (m, 1H), 3.94-3.04 (m, 4H), 2.52-2.20 (m, 4H),2.20-1.86 (m, 6H). 38

N-(1-(2-(pyrrolidin-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)cyclohexanecarboxamide maleate ¹H NMR (CD₃OD) δ ppm: 8.66 (s, 1H),8.64 (s, 1H), 6.24 (s, 2H), 4.85 (t, J = 5.6 Hz, 2H), 3.83 (t, J = 5.6Hz, 2H), 3.48-3.19 (m, 4H), 2.60 (tt, J = 11.7, 3.6 Hz, 1H), 2.21-1.68(m, 9H), 1.65-1.24 (m, 5H). 39

N-(1-(2-(pyrrolidin-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)cyclopentanecarboxamide maleate ¹H NMR (CD₃OD) δ ppm: 8.68 (s, 1H),8.65 (s, 1H), 6.24 (s, 2H), 4.85 (t, J = 5.6 Hz, 2H), 3.83 (t, J = 5.6Hz, 2H), 3.61-3.20 (m, 4H), 3.09-3.02 (m, 1H), 2.18-1.59 (m, 12H). 40

N-(1-(2-(pyrrolidin-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)cyclopropanecarboxamide maleate ¹H NMR (CD₃OD) δ ppm: 8.63 (s, 1H),8.61 (s, 1H), 6.22 (s, 2H), 4.79 (t, J = 5.9 Hz, 2H), 3.65 (t, J = 5.9Hz, 2H), 3.44-3.20 (m, 4H), 2.22-1.75 (m, 5H), 1.18-1.05 (m, 2H),1.05-0.93 (m, 2H). 41

N-(1-(4-(azepan-1- yl)butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide maleate ¹H NMR (CD₃OD) δ ppm: 8.62 (s, 1H),8.55 (s, 1H), 6.24 (s, 2H), 4.53 (t, J = 6.6 Hz, 2H), 3.29-3.22 (m, 4H),3.22-3.13 (m, 2H), 2.02 (q, J = 7.0 Hz, 2H), 1.95-1.81 (m, 4H),1.79-1.60 (m, 6H), 1.38 (s, 9H). 42

N-(1-(3-(azepan-1- yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide maleate ¹H NMR (CD₃OD) δ ppm: 8.64 (s, 1H),8.58 (s, 1H), 6.25 (s, 2H), 4.59 (t, J = 6.4 Hz, 1H), 3.52-3.33 (m, 2H),3.27-3.16 (m, 4H), 2.48-2.30 (m, 2H), 1.98-1.80 (m, 4H), 1.78-1.66 (m,4H), 1.38 (s, 9H). 43

N-(1-(2-((3S,5R)-3,5- dimethylpiperazin-1- yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide ¹H NMR (CD₃OD) δ ppm: 8.60 (s, 1H), 8.53 (s,1H), 4.61 (t, J = 6.6 Hz, 2H), 2.96-2.89 (m, 2H), 2.89 (t, J = 6.5 Hz,2H), 2.81-2.62 (m, 2H), 1.72 (t, J = 10.9 Hz, 2H), 1.38 (s, 9H), 1.04(d, J = 6.5 Hz, 6H).

Example 44 Synthesis of1-(1-(2-(1,4-oxazepan-4-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea

1-(2-(1,4-oxazepan-4-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(0.039 g, 0.149 mmol), propyl isocyanate (0.032 g, 0.376 mmol) in 3 mLof toluene were heated in CEM microwave reactor for 20 minutes at 140°C. The mixture was concentrated under reduced pressure, treated withacetonitrile and filtered to afford 6 mg of1-(1-(2-(1,4-oxazepan-4-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea.¹H NMR (CD₃OD) δ ppm: 8.54 (s, 1H), 8.34 (s, 1H), 4.55 (t, J=6.3 Hz,2H), 3.66 (t, J=5.6 Hz, 2H), 3.62-3.52 (m, 2H), 3.42-3.26 (m, 2H), 3.08(t, J=6.3 Hz, 2H), 2.79-2.63 (m, 4H), 1.84-1.71 (m, 2H), 1.72-1.57 (m,2H), 1.01 (t, J=7.3 Hz, 3H).

Examples (45-74) were prepared following the same method as example 44:

Ex. Structure Name NMR 45

1-tert-Butyl-3-(1-(2- morpholinoethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.65 (s, 1H),8.59 (s, 1H), 4.98 (t, J = 5.9 Hz, 2H), 4.20-3.97 (m, 2H), 3.84 (t, J =5.9 Hz, 2H), 3.91- 3.57 (m, 4H), 3.34-3.19 (m, 2H), 1.46 (s, 9H). 46

1-Cyclohexyl-3-(1-(2- morpholinoethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.66 (s, 1H),8.58 (s, 1H), 4.97 (t, J = 5.9 Hz, 2H), 4.20-3.98 (m, 2H), 3.84 (t, J =5.9 Hz, 2H), 3.88- 3.60 (m, 4H), 3.38-3.17 (m, 2H), 2.05-1.91 (m, 1H),1.90-1.57 (m, 4H), 1.55-1.08 (m, 6H). 47

1-Adamanthyl-3-(1-(2- morpholinoethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.64 (s, 1H),8.58 (s, 1H), 4.97 (t, J = 5.9 Hz, 2H), 4.17-3.98 (m, 2H), 3.84 (t, J =5.9 Hz, 2H), 3.93- 3.59 (m, 4H), 3.41-3.15 (m, 2H), 2.23-2.03 (m, 9H),1.86-1.69 (m, 6H). 48

1-(1-(2-(Azepan-1- yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-ethylurea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.67 (s, 1H), 8.59 (s,1H), 4.95 (t, J = 6.0 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.69-3.56 (m,2H), 3.47- 3.35 (m, 4H), 2.15- 1.84 (m, 4H), 1.84-1.69 (m, 4H), 1.25 (t,J = 7.2 Hz, 3H). 49

1-(1-(2-(Azepan-1- yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-cyclopentylurea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.67 (s, 1H), 8.61(s, 1H), 4.95 (t, J = 5.9 Hz, 2H), 4.31-4.13 (m, 1H), 3.83 (t, J = 6.0Hz, 2H), 3.69- 3.55 (m, 2H), 3.40-3.29 (m, 2H), 2.18-1.86 (m, 6H),1.86-1.49 (m, 10H). 50

1-(2,4-Dichlorophenyl)- 3-(1-(2- morpholinoethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (DMSO-d₆) δ ppm: 11.3 (s,1H), 10.1 (s, 1H), 8.75 (s, 1H), 8.6 (s, 1H), 8.4 (d, J = 8.9 Hz, 1H),7.7 (d, J = 2.4 Hz, 1H), 7.45 (dd, J = 9.0 Hz, 2.5 Hz, 1H), 4.8 (m, 2H),3.95 (m, 2H), 3.65 (m, 4H), 3.5 (m, 2H), 3.15 (m, 2H). 51

1-(1-(2-(Azepan-1- yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-cyclohexylurea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.67 (s, 1H), 8.61(s, 1H), 4.95 (t, J = 5.8 Hz, 2H), 3.83 (t, J = 5.9 Hz, 2H), 3.79-3.71(m, 1H), 3.68- 3.53 (m, 2H), 3.41- 3.30 (m, 2H), 2.08-1.84 (m, 6H),1.84-1.70 (m, 6H), 1.70-1.58 (m, 1H), 1.54-1.24 (m, 5H). 52

1-(1-(2- (Diisopropylamino)ethyl)- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)-3-ethylurea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.68 (s, 1H), 8.61 (s,1H), 4.92 (t, J = 7.3 Hz, 2H), 3.90 (hept, J = 6.5 Hz, 2H), 3.75 (t, J =7.3 Hz, 2H), 3.40 (q, J = 7.2 Hz, 2H), 1.46 (d, J = 6.5 Hz, 12H), 1.25(t, J = 7.2 Hz, 3H). 53

1-Cyclopentyl-3-(1-(2- (diisopropylamino)ethyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.65 (s, 1H),8.6 (s, 1H), 4.95 (t, J = 7.3 Hz, 2H), 4.2 (m, 1H), 3.9 (m, 2H), 3.75(t, J = 7.4 Hz, 2H), 2.05 (m, 2H), 1.65-1.45 (m, 6H), 1.45 (d, J = 6.6Hz, 12H). 54

1-Cyclopentyl-3-(1-(2- (piperidin-1-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.65 (s, 1H),8.6 (s, 1H), 4.95 (t, J = 6.0 Hz, 2H), 4.2 (m, 1H), 3.75 (m, 4H), 3.05(t, J = 12.4 Hz, 2H), 2.05 (m, 4H), 1.95-1.5 (m, 10H). 55

1-Ethyl-3-(1-(2- (piperidin-1-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.65 (s, 1H),8.6 (s, 1H), 4.95 (t, J = 5.9 Hz, 2H), 3.75 (m, 4H), 3.4 (q, J = 7.2 Hz,2H), 3.05 (t, J = 11.0 Hz, 2H), 2.0 (m, 2H), 1.8 (m, 3H), 1.55 (m, 1H),1.25 (t, J = 7.2 Hz, 3H). 56

1-Adamanthyl-3-(1-(2- (piperidin-1-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.65 (s, 1H),8.6 (s, 1H), 4.95 (t, J = 5.9 Hz, 2H), 3.75 (m, 4H), 3.05 (t, J = 12.3Hz, 2H), 2.15 (m, 9H), 2.0 (m, 2H), 1.55 (m, 10H). 57

1-Cyclohexyl-3-(1-(2- (diisopropylamino)ethyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.65 (s, 1H),8.52 (s, 1H), 4.89 (t, J = 7.2 Hz, 2H), 3.91 (hept, J = 6.6 Hz, 2H),3.75 (t, J = 7.2 Hz, 2H), 3.72-3.56 (m, 1H), 2.09-1.89 (m, 2H), 1.89-1.75 (m, 2H), 1.73- 1.56 (m, 1H), 1.45 (dd, J = 6.5, 1.6 Hz, 12H), 1.62-1.20 (m, 5H). 58

1-(2,4-Dichlorophenyl)- 3-(1-(2- (diisopropylamino)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δppm: 8.74 (s, 1H), 8.53 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 7.56 (d, J =1.8 Hz, 1H), 7.36 (dd, J = 8.7, 2.1 Hz, 1H), 4.90 (t, J = 7.2 Hz, 2H),3.91 (hept, J = 6.7 Hz, 2H), 3.76 (t, J = 7.2 Hz, 2H), 1.46 (d, J = 6.4Hz, 12H). 59

1-Cyclohexyl-3-(1-(2- (piperidin-1-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.65 (s, 1H),8.55 (s, 1H), 4.95 (t, J = 6.0 Hz, 2H), 3.75 (m, 4H), 3.1 (t, J = 12.3Hz, 2H), 2.0 (m, 4H), 1.85-1.15 (m, 13H). 60

1-(2,4-Dichlorophenyl)- 3-(1-(2-(piperidin-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δ ppm:8.75 (s, 1H), 8.55 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 2.3Hz, 1H), 7.4 (dd, J = 8.9 Hz, 2.4 Hz, 1H), 4.95 (t, J = 6.0 Hz, 2H),3.75 (m, 4H), 3.1 (t, J = 12.3 Hz, 2H), 2.0 (m, 2H), 1.9-1.75 (m, 3H),1.55 (m, 1H). 61

1-tert-Butyl-3-(1-(2- (diisopropylamino)ethyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.63 (s, 1H),8.55 (s, 1H), 4.97-4.84 (m, 2H), 3.90 (hept, J = 6.6 Hz, 2H), 3.78-3.71(m, 2H), 1.46 (s, 9H), 1.45 (d, J = 6.5 Hz, 12H). 62

1-(1-(2-(azepan-1- yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-tert-butylurea hydrochloride ¹H NMR (DMSO-d₆) δ ppm: 10.25 (s, 1H), 8.98 (s,1H), 8.61 (s, 1H), 8.58 (s, 1H), 4.82 (t, J = 6.3 Hz, 2H), 3.50-3.34 (m,4H), 3.26-3.07 (m, 2H), 1.87-1.73 (m, 4H), 1.71- 1.50 (m,4H), 1.38 (s,9H). 63

1-Adamanthyl-3-(1-(2- (azepan-1-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)urea maleate ¹H NMR (CD₃OD) δ ppm: 8.57 (s, 1H), 8.45(s, 1H), 6.26 (s, 2H), 4.85 (t, J = 5.9 Hz, 2H), 3.79 (t, J = 5.9 Hz,2H), 3.70-3.07 (m, 4H), 2.22-2.04 (m, 9H), 2.04-1.86 (m, 4H), 1.86-1.61(m, 10H). 64

1-(1-(2-(azepan-1- yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-(2,4-dichlorophenyl)urea citrate ¹H NMR (CD₃OD) δ ppm: 7.89 (s, 1H), 7.65 (s,1H), 7.56 (d, J = 9.0 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 6.54 (dd, J =9.0, 2.4 Hz, 1H), 3.99 (t, J = 6.1 Hz, 2H), 2.84 (t, J = 6.0 Hz, 2H),2.68-2.35 (m, 4H), 1.97 (q, J = 15.4 Hz, 4H), 1.20-0.97 (m, 4H), 0.97-0.76 (m, 4H). 65

1-(1-(2-(azepan-1- yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-(2,4,4-trimethylpentan- 2-yl)urea maleate ¹H NMR (CD₃OD) δ ppm: 8.58 (s,1H), 8.44 (s, 1H), 6.24 (s, 2H), 4.84 (t, J = 5.8 Hz, 2H), 3.70 (t, J =5.8 Hz, 2H), 3.43-3.34 (m, 4H), 1.99-1.82 (m, 4H), 1.87 (s, 2H), 1.81-1.60 (m, 4H), 1.51 (s, 6H), 1.05 (s, 9H). 66

1-(1-(2-(azepan-1- yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-propylurea maleate ¹H NMR (CD₃OD) δ ppm: 8.60 (s, 1H), 8.44 (s, 1H),6.27 (s, 2H), 4.87 (t, J = 5.9 Hz, 2H), 3.79 (t, J = 5.9 Hz, 2H),3.69-3.12 (m, 4H), 3.38-3.32 (m, 2H), 2.03-1.85 (m, 4H), 1.85-1.71 (m,4H), 1.71- 1.57 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). 67

1-(1-(2-(azepan-1- yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-butylurea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.67 (s, 1H), 8.60 (s,1H), 4.95 (t, J = 6.0 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.69-3.54 (m,2H), 3.45- 3.33 (m, 2H), 3.37 (t, J = 7.0 Hz, 2H), 2.05-1.86 (m, 4H),1.82-1.71 (m, 4H), 1.69-1.54 (m, 2H), 1.44 (dq, J = 14.2, 7.1 Hz, 2H),0.99 (t, J = 7.3 Hz, 3H). 68

1-(1-(2-(azepan-1- yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-cyclopropylurea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.65 (s, 1H), 8.57(s, 1H), 4.93 (t, J = 5.9 Hz, 2H), 3.82 (t, J = 5.9 Hz, 2H), 3.74-3.49(m, 2H), 3.43- 3.28 (m, 2H), 2.91- 2.67 (m, 1H), 2.09-1.82 (m, 4H),1.85-1.68 (m, 4H), 0.94-0.75 (m, 2H), 0.73-0.57 (m, 2H). 69

1-(1-(2-(azepan-1- yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-isopropylurea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.67 (s, 1H), 8.61 (s,1H), 4.95 (t, J = 6.0 Hz, 2H), 4.04 (hept, J = 6.6 Hz, 1H), 3.83 (t, J =6.0 Hz, 2H), 3.74-3.52 (m, 2H), 3.43-3.26 (m, 2H), 2.11- 1.84 (m, 4H),1.84- 1.63 (m, 4H), 1.29 (d, J = 6.6 Hz, 6H). 70

1-isopropyl-3-(1-(2- (pyrrolidin-1-yl)ethyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.67 (s, 1H),8.61 (s, 1H), 4.92 (t, J = 5.7 Hz, 2H), 4.04 (hept, J = 6.6 Hz, 1H),3.87 (d, J = 5.7 Hz, 2H), 3.82-3.69 (m, 2H), 3.26-3.09 (m, 2H), 2.30-2.10 (m, 2H), 2.10- 1.89 (m, 2H), 1.29 (d, J = 6.6 Hz, 6H). 71

1-propyl-3-(1-(2- (pyrrolidin-1-yl)ethyl)- 1 H-pyrazolo[3,4-d]pyrimidin-4-yl)urea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.67 (s, 1H),8.60 (s, 1H), 4.92 (t, J = 5.7 Hz, 2H), 3.87 (t, J = 5.7 Hz, 2H),3.81-3.72 (m, 2H), 3.32 (t, J = 6.9 Hz, 2H), 3.27- 3.08 (m, 2H),2.27-2.09 (m, 2H), 2.09-1.95 (m, 2H), 1.79-1.51 (m, 2H), 1.01 (t, J =7.4 Hz, 3H). 72

1-(1-(4-(azepan-1- yl)butyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-propylurea maleate ¹H NMR (CD₃OD) δ ppm: 8.56 (s, 1H), 8.36 (s, 1H),6.25 (s, 2H), 4.50 (t, J = 6.7 Hz, 3H), 3.41-3.30 (m, 2H), 3.13-3.00 (m,4H), 3.00-2.86 (m, 2H), 2.08-1.91 (m, 2H), 1.87- 1.73 (m, 4H), 1.73-1.52 (m, 8H), 1.01 (t, J = 7.4 Hz, 3H). 73

1-(1-(3-(azepan-1- yl)propyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-propylurea ¹H NMR (CD₃OD) δ ppm: 8.55 (s, 1H), 8.34 (s, 1H), 4.48 (t, J= 6.8 Hz, 2H), 3.44-3.28 (m, 2H), 2.69- 2.58 (m, 4H), 2.58- 2.46 (m,2H), 2.24-2.01 (m, 2H), 1.78-1.48 (m, 10H), 1.02 (t, J = 7.4 Hz, 3H). 74

1-(1-(2-(4-tert- butylpiperidin-1- yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-3- propylurea ¹H NMR (CD₃OD) δ ppm: 8.55 (s, 1H), 8.34(s, 1H), 4.59 (t, J = 6.8 Hz, 2H), 3.43-3.29 (m, 2H), 3.19- 3.01 (m,2H), 2.88 (t, J = 6.8 Hz, 2H), 2.15-1.93 (m, 2H), 1.76-1.53 (m, 4H),1.44-1.16 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H), 0.85 (s, 9H).

Example 75 Synthesis of1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-butylthioureamaleate

1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g,0.384 mmol), propyl thioisocyanate (0.133 g, 1.154 mmol) in 4 mL oftoluene were heated in CEM microwave reactor for 60 min. at 150° C. Themixture was concentrated under reduced pressure, purified by flashchromatography (EtOAc) treated with acetonitrile and filtered to afford23 mg of a white solid. To an ice-cooled stirred solution of1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-butylthioureain 0.5 mL of MeOH, 7.5 mg of maleic acid in 0.5 mL of MeOH was addeddropwise. After stirring for 15 minutes at rt, the solid was filtered,and the residue washed with diethyl ether to obtain 26 mg of1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-butylthioureamaleate. ¹H NMR (CD₃OD) δ ppm: 8.63 (s, 1H), 8.53 (s, 1H), 6.24 (s, 2H),4.89 (t, J=5.9 Hz, 2H), 3.79 (t, J=5.9 Hz, 2H), 3.75 (t, J=7.1 Hz, 2H),3.57-3.39 (m, 4H), 2.01-1.85 (m, 4H), 1.85-1.65 (m, 6H), 1.49 (dq,J=14.3, 7.3 Hz, 2H), 1.01 (t, J=7.3 Hz, 3H).

Examples (76-79) were prepared following the same method as example 75:

Ex. Structure Name NMR 76

1-(1-(2-(azepan- 1-yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-methylthiourea maleate ¹H NMR (CD₃OD) δ ppm: 8.63 (s, 1H), 8.53 (s,1H), 6.25 (s, 2H), 4.89 (t, J = 5.9 Hz, 2H), 3.79 (t, J = 5.9 Hz, 2H),3.66-2.99 (m, 4H), 3.25 (s, 3H), 2.06- 1.83 (m, 4H), 1.83- 1.66 (m, 4H).77

1-(1-(2-(azepan- 1-yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-propylthiourea ¹H NMR (CDCl₃) δ ppm: 12.01-11.72 (m, 1H), 8.54 (s,1H), 8.35 (s, 1H), 8.05 (s, 1H), 4.63-4.43 (m, 2H), 3.74 (dd, J = 12.4,6.9 Hz, 2H), 3.23-2.99 (m, 2H), 2.89-2.53 (m, 4H), 1.95-1.72 (m, 2H),1.62-1.44 (m, 8H), 1.07 (t, J = 7.4 Hz, 3H). 78

1-(1-(2-(azepan- 1-yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-ethylthiourea ¹H NMR (CD₃OD) δ ppm: 8.58 (s, 1H), 8.43 (s, 1H), 4.57(t, J = 6.6 Hz, 2H), 3.77 (q, J = 7.3 Hz, 2H), 3.10 (t, J = 6.6 Hz, 2H),2.87- 2.62 (m, 4H), 1.73- 1.47 (m, 8H), 1.34 (t, J = 7.3 Hz, 3H). 79

1-(1-(2-(azepan- 1-yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-cyclopropylthiourea hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.63 (s, 1H),8.54 (s, 1H), 4.90 (t, J = 5.9 Hz, 2H), 3.80 (t, J = 5.9 Hz, 2H),3.72-3.52 (m, 2H), 3.34-3.11 (m, 1H), 3.43-3.08 (m, 2H), 2.21-1.82 (m,4H), 1.82-1.66 (m, 4H), 1.08-0.85 (m, 2H), 0.85-0.69 (m, 2H).

Example 80 Synthesis of2,4-Dichloro-N-(1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzenesulfonamidehydrochloride

To a solution of NaH (9.15 mg, 0.381 mmol) in 3 ml of anhydrous DMF, wasadded dropwise a solution of1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100mg, 0.381 mmol) in 2 mL of anhydrous DMF at 0° C. The mixture wasstirred at 50° C. for 1 h. Then, sulfonyl chloride (98 mg, 0.400 mmol)in 1 ml anhydrous DMF was added and the mixture was heated at 60° C. for26 h. The reaction mixture was cooled to rt and stirred for twoadditional days, 1 ml water was added and the solvent evaporated todryness. The crude was partitioned between EtOAc and water. The organiclayer was dried and evaporated under vacuum and purified by flashchromatography (EtOAc/MeOH=10:1). 1 ml of a 4M solution of dioxane.HClwas added to a solution of 1 in 1.5 ml of anhydrous DCM, at 0° C. After15 minutes the product was evaporated to dryness, treated with diethylether, and filtered to obtain 15 mg of a white solid. ¹H NMR (CD₃OD) δppm: 8.54 (s, 1H), 8.31 (s, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.68 (d, J=1.9Hz, 1H), 7.54 (dd, J=8.5, 2.0 Hz, 1H), 4.81 (t, J=7.2 Hz, 2H), 3.90(hept, J=6.6 Hz, 2H), 3.73 (t, J=7.2 Hz, 2H), 1.44 (d, J=6.6 Hz, 12H).

Example (81) was prepared following same method as example 80:

Ex. Structure Name NMR 81

N-(1-(2- (Diisopropylamino)ethyl)- 1H-pyrazolo[3,4- d]pyrimidin-4-yl)cyclohexanesulfonamide hydrochloride ¹H NMR (CD₃OD) δ ppm: 8.53 (s,1H), 8.24 (s, 1H), 4.79 (t, J = 7.2 Hz, 2H), 3.89 (hept, J = 6.6 Hz,2H), 3.78-3.63 (m, 3H), 3.11-2.94 (m, 1H), 2.36- 2.22 (m, 2H), 1.98-1.84 (m, 2H), 1.81-1.68 (m, 1H), 1.68-1.49 (m, 2H), 1.44 (d, J = 6.6 Hz,12H), 1.47-1.16 (m, 2H).

Examples (82-88) were prepared following the same method as in example1:

Ex. Structure Name NMR 82

N-(1-(2-(4-tert- butylpiperidin-1-yl)ethyl)- 1H-pyrazolo[3,4-d]pyrimidin-4- yl)pivalamide ¹H NMR (CD₃OD) δ ppm: 8.61 (s, 1H), 8.54(s, 1H), 4.61 (t, J = 6.9 Hz, 2H), 3.09 (dt, J = 11.8, 3.1 Hz, 2H), 2.89(t, J = 6.9 Hz, 2H), 2.02 (td, J = 12.0, 2.0 Hz, 2H), 1.75-1.59 (m, 2H),1.38 (s, 9H), 1.26 (qd, J = 12.4, 3.7 Hz, 2H), 1.09-0.93 (m, 1H), 0.85(s, 9H). 83

N-(1-(2-(1,4-oxazepan-4- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)pivalamide ¹H NMR (CDCl₃) δ ppm: 8.70 (s, 1H), 8.57 (s, 1H), 8.33 (s,1H), 4.88-4.42 (m, 2H), 3.91-3.55 (m, 4H), 3.31-3.02 (m, 2H), 2.99-2.67(m, 4H), 2.07- 1.74 (m, 2H), 1.39 (s, 9H). 84

N-(1-(2-(4-methyl-1,4- diazepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)pivalamide ¹H NMR (CDCl₃) δ ppm: 8.69 (s,1H), 8.57 (s, 1H), 8.33 (s, 1H), 4.55 (t, J = 6.7 Hz, 2H), 3.08 (t, J =6.7 Hz, 2H), 2.86-2.72 (m, 4H), 2.63-2.49 (m, 4H), 2.32 (s, 3H), 1.84-1.73 (m, 2H), 1.39 (s, 9H). 85

N-(1-(3-(piperidin-1- yl)propyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide ¹H NMR (CD₃OD) δ ppm: 8.61 (s, 1H), 8.53 (s, 1H), 4.50(t, J = 6.7 Hz, 2H), 2.53-2.33 (m, 6H), 2.24- 2.07 (m, 2H), 1.65- 1.50(m, 4H), 1.50-1.42 (m, 2H), 1.38 (s, 9H). 86

N-(1-(3-(4- methylpiperazin-1- yl)propyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide ¹H NMR (CD₃OD) δ ppm: 8.61 (s, 1H), 8.53 (s, 1H), 4.52(t, J = 6.7 Hz, 2H), 2.85-2.30 (m, 10H), 2.25 (s, 3H), 2.17-2.05 (m,2H), 1.38 (s, 9H). 87

N-(1-(2-(4- methylpiperazin-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)pivalamide maleate ¹H NMR (CD₃OD) δ ppm: 8.60 (s, 1H), 8.53 (s, 1H),6.28 (s, 4H), 4.61 (t, J = 6.0 Hz, 2H), 3.29-2.38 (m, 4H), 3.01 (t, J =6.0 Hz, 2H), 2.80 (s, 3H), 1.37 (s, 9H). 88

N-(1-(4-(4-tert- butylpiperidin-1-yl)butyl)- 1H-pyrazolo[3,4-d]pyrimidin-4- yl)pivalamide maleate ¹H NMR (CD₃OD) δ ppm: 8.63 (s, 1H),8.55 (s, 1H), 6.25 (s, 2H), 4.54 (t, J = 6.6 Hz, 2H), 3.63-3.45 (m, 2H),3.20-3.03 (m, 2H), 2.87 (t, J= 12.6 Hz, 2H), 2.12-1.88 (m, 4H),1.79-1.63 (m, 2H), 1.57- 1.42 (m, 3H), 1.38 (s, 9H), 0.91 (s, 9H).

Examples (89-95) were prepared following the same method as in example44:

Ex. Structure Name NMR 89

1-(1-(2-(4-methyl-1,4- diazepan-1-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-3- propylurea ¹H NMR (CD₃OD) δ ppm: 8.55 (s, 1H), 8.35(s, 1H), 4.53 (t, J = 6.3 Hz, 2H), 3.41-3.32 (m, 2H), 3.06 (t, J = 6.4Hz, 2H), 2.82- 2.69 (m, 4H), 2.55-2.44 (m, 4H), 2.23 (s, 3H), 1.79- 1.58(m, 4H), 1.02 (t, J = 7.4 Hz, 3H). 90

1-(1-(3-(4- methylpiperazin-1- yl)propyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-3- propylurea ¹H NMR (CD₃OD) δ ppm: 8.55 (s, 1H), 8.34(s, 1H), 4.49 (t, J = 6.7 Hz, 2H), 3.36-3.32 (m, 2H), 2.68- 2.19 (m,8H), 2.42- 2.33 (m, 2H), 2.24 (s, 3H), 2.16-2.04 (m, 2H), 1.73- 1.58 (m,2H), 1.02 (t, J = 7.4 Hz, 4H). 91

1-(1-(3-(piperidin-1- yl)propyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-propylurea ¹H NMR (CD₃OD) δ ppm: 8.55 (s, 1H), 8.34 (s, 1H), 4.48 (t, J= 6.7 Hz, 2H), 3.38-3.30 (m, 2H), 2.51- 2.28 (m, 6H), 2.22- 2.04 (m,2H), 1.66 (h, J = 7.3 Hz, 2H), 1.56 (p, J = 5.6 Hz, 4H), 1.52-1.38 (m,2H), 1.02 (t, J = 7.4 Hz, 3H). 92

1-(1-(2-(4- methylpiperazin-1- yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-3- propylurea ¹H NMR (CD₃OD) δ ppm: 8.54 (s, 1H), 8.34(s, 1H), 4.58 (t, J = 6.5 Hz, 2H), 3.34 (t, J = 7.0 Hz, 2H), 2.91 (t, J= 6.5 Hz, 2H), 2.71-2.49 (m, 4H), 2.46- 2.28 (m, 4H), 2.22 (s, 3H), 1.66(h, J =7.4 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H). 93

1-(1-(4-(4-tert- butylpiperidin-1- yl)butyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-3- propylurea ¹H NMR (CD₃OD) δ ppm: 8.54 (s, 1H), 8.34(s, 1H), 4.46 (t, J = 6.8 Hz, 2H), 3.36-3.31 (m, 2H), 3.03- 2.93 (m,2H), 2.42- 2.34 (m, 2H), 1.93 (dt, J = 14.7, 6.9 Hz, 4H), 1.72- 1.60 (m,4H), 1.54-1.42 (m, 2H), 1.30 (qd, J = 12.7, 3.6 Hz, 2H), 1.09- 1.04 (m,1H), 1.01 (t, J = 7.4 Hz, 3H), 0.85 (s, 9H). 94

1-(1-(2-(4- acetylpiperazin-1- yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-3- propylurea ¹H NMR (CD₃OD) δ ppm: 8.55 (s, 1H), 8.35(s, 1H), 4.59 (t, J = 6.3 Hz, 2H), 3.49-3.42 (m, 2H), 3.42- 3.37 (m,2H), 3.37- 3.32 (m, 2H), 2.92 (t, J = 6.3 Hz, 2H), 2.58-2.52 (m, 2H),2.52-2.46 (m, 2H), 2.05 (s, 3H), 1.66 (h, J = 7.4 Hz, 2H), 1.02 (t, J =7.4 Hz, 3H). 95

1-(1-(2-(piperidin-1- yl)ethyl)-1H- pyrazolo[3,4- d]pyrimidin-4-yl)-3-propylurea ¹H NMR (CD₃OD) δ ppm: 8.54 (s, 1H), 8.34 (s, 1H), 4.58 (t, J= 6.8 Hz, 2H), 3.37-3.31 (m, 2H), 2.87 (t, J = 6.8 Hz, 2H), 2.55- 2.46(m, 4H), 1.65 (h, J = 7.3 Hz, 2H), 1.59-1.49 (m, 4H), 1.48-1.38 (m, 2H),1.01 (t, J = 7.4 Hz, 3H).

Examples (96-100) were prepared following same method as in example 80:

Ex. Structure Name NMR  96

2,4-dichloro-N-(1-(2- (piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin- 4-yl)benzenesulfonamide ¹H NMR (CDCl₃) δ ppm:8.19 (d, J = 8.5 Hz, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.50 (d, J = 2.1Hz, 1H), 7.42 (dd, J = 8.6, 2.0 Hz, 1H), 4.92-4.42 (m, 2H), 3.23-2.95(m, 2H), 2.81- 2.32 (m, 4H), 1.92- 1.17 (m, 6H).  97

N-(1-(2-(piperidin-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)methanesulfonamide ¹H NMR (CDCl₃) δ ppm 8.21 (s, 1H), 8.02 (s, 1H),4.50 (t, J = 6.8 Hz, 2H), 3.15 (s, 3H), 2.83 (t, J = 6.8 Hz, 2H), 2.45(t, J = 5.2 Hz, 4H), 1.57-1.45 (m, 4H), 1.45-1.32 (m, 2H).  98

N-(1-(2-(piperidin-1- yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)propane- 2-sulfonamide ¹H NMR (CDCl₃) δ ppm: 8.16 (s,1H), 7.97 (s, 1H), 4.57 (t, J = 6.9 Hz, 2H), 3.31 (p, J = 6.8 Hz, 1H),2.99-2.91 (m, 2H), 2.68- 2.44 (m, 4H), 1.71- 1.53 (m, 4H), 1.47-1.40 (m,2H), 1.43 (d, J = 6.9 Hz, 6H).  99

N-(1-(2-(piperidin-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)cyclohexanesulfonamide ¹H NMR (CDCl₃, ca 1.4:1 rotamer mixture) δ ppm:8.31/8.15 (2 x s, 1H), 7.93/7.92 (2 x s, 1H), 4.56/4.48 (2 x t, J = 6.5;5.4 Hz, 2H), 3.12-2.82 (m, 3H), 2.63-2.41 (m, 4H), 2.27 (m, 2H), 1.98-1.08 (m, 14H). 100

N-(1-(2-(piperidin-1- yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)ethanesulfonamide ¹H NMR (CD₃OD) δ ppm: 8.33 (s, 1H), 8.21 (s, 1H),4.59 (t, J = 6.4 Hz, 2H), 3.32-3.22 (m, 2H), 3.09 (t, J = 6.4 Hz, 2H),2.81- 2.70 (m, 4H), 1.72-1.57 (m, 4H), 1.57-1.45 (m, 2H), 1.39 (t, J =7.4 Hz, 3H).

Example 101 Synthesis ofN-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylacetamideStep 1.—1-(2-(azepan-1-yl)ethyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine

1-(2-(azepan-1-yl)ethyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (100 mg,0.65 mmol) in anh. DMF (2 mL) was added to a suspension of NaH (91 mg,60% dispersión in mineral oil) in anh. DMF (3 mL) at 0° C. The mixturewas stirred at room temperature for 45 min. Then,1-(2-chloroethyl)azepane hydrochloride (192 mg, 0.97 mmol) in portionsat −15° C. and was kept at this temperature for 3 h. The solvent wasevaporated to dryness and the residue was diluted in ethyl ether,filtered and the solvent was removed under reduced pressure. The crudewas purified by flash chromatography to give1-(2-(azepan-1-yl)ethyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (40 mg,0.14 mmol, 22%) as an oil.

Step2.—1-(2-(azepan-1-yl)ethyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A solution of1-(2-(azepan-1-yl)ethyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (40 mg,0.14 mmol) in methylamine 33% in ethanol was stirred at room temperaturemonitoring the reaction by TLC. The solvent was removed under reducedpressure to give1-(2-(azepan-1-yl)ethyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(39 mg, 0.14 mmol, quantitative) as an oil.

Step3.—N-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylacetamide

A mixture of1-(2-(azepan-1-yl)ethyl)-N-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine(20 mg, 0.07 mmol) and acetic anhydride (74 mg, 0.72 mmol) in pyridine(2 mL) was stirred at 130° C. for 15 min under microwave irradiation(150 W). Ice was added and the solvent concentrated to dryness. Theresidue was diluted in EtOAc, washed with water, separated and removedunder reduced pressure to give an oil that was purified by flashchromatography yieldingN-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylacetamide(6 mg, 0.02 mmol, 27%). ¹H NMR (CDCl₃) δ ppm: 8.75 (s, 1H), 8.07 (s,1H), 4.60 (t, J=6.9 Hz, 2H), 3.62 (s, 3H), 3.12 (t, J=7.0 Hz, 2H),2.89-2.66 (m, 4H), 2.44 (s, 3H), 1.68-1.56 (m, 4H), 1.56-1.45 (m, 4H).

Example 102 Synthesis of1-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyrrolidin-2-one

A mixture of4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (50mg, 0.19 mmol), pyrrolidin-2-one (0.07 mL), palladium diacetate (4.22mg, 1.7 mmol), Xantphos (16 mg, 2.7 mmol) and cesium carbonate (67 mg,0.20 mmol) in dry toluene (3 mL) in a microwave vial was degassed byargon for 30 minutes. The mixture was stirred at 120° C. for 20 minunder microwave irradiation (150 W). The reaction was monitores by TLC.The mixture was filtered on decalite and the solvent was removed underreduced pressure. The crude was purified by flash chromatography to give1-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyrrolidin-2-one(12 mg, 0.038 mmol, 20% yield). ¹H NMR (CDCl₃) δ ppm: 8.68 (s, 1H), 8.63(s, 1H), 4.63 (t, J=7.1 Hz, 2H), 4.25-4.15 (m, 2H), 2.93 (t, J=7.1 Hz,2H), 2.75 (t, J=8.1 Hz, 2H), 2.61-2.41 (m, 4H), 2.24 (p, J=7.7 Hz, 2H),1.65-1.47 (m, 4H), 1.48-1.36 (m, 2H).

Example 103 Synthesis of4-(1H-imidazol-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine

Potassium tert-butoxide (51 mg, 0.45 mmol) was added to a solution of1H-imidazole (31 mg, 0.45 mmol) in acetonitrile (5 mL) at roomtemperature and the mixture was stirred for 15 min. Then,4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (100mg, 0.37 mmol) was added and the mixture was stirred overnight. Water(0.5 mL) was added and the solvent was removed at reduced pressure. Theresulting solid was extracted with dichloromethane and the organic phasewas washed with brine and removed under reduced pressure to give4-(1H-imidazol-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine(110 mg, 0.37 mmol, quantitative) as a pale yellow solid. ¹H NMR (CDCl₃)δ ppm: 8.83 (s, 1H), 8.66 (t, J=1.1 Hz, 1H), 8.26 (s, 1H), 7.93 (t,J=1.4 Hz, 1H), 7.42-7.29 (m, 1H), 4.86-4.63 (m, 2H), 3.13-2.87 (m, 2H),2.70-2.40 (m, 4H), 1.71-1.51 (m, 4H), 1.51-1.31 (m, 2H).

Examples 104 was prepared following the same method as in example 103:

Ex. Structure Name NMR 104

4-(1H-benzo[d]imidazol-1- yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidine ¹H NMR (CD₃OD) δ ppm: 9.18 (s,1H), 8.99 (s, 1H), 8.72-8.58 (m, 2H), 7.82 (dd, J = 6.9, 2.4 Hz, 1H),7.56-7.38 (m, 2H), 4.73 (t, J = 6.8 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H),2.55 (t, J = 5.0 Hz, 4H), 1.63-1.48 (m, 4H), 1.48-1.35 (m, 2H).

Example 105 Synthesis of4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine

A mixture of1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg,0.20 mmol) in hexane-2,5-dione (1.5 mL) was stirred at 180° C. for 20min under microwave irradiation (150 W). The mixture was acidified withdiluted HCl 1N and extracted with DCM. The aqueous phase was basifiedwith NaOH 20% and extracted with DCM. The organic phase was removedunder reduced pressure and the residue was purified by flashchromatography to give4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine(21 mg, 0.06 mmol, 32%), as a brown solid. ¹H NMR (CDCl₃) δ ppm: 8.85(s, 1H), 8.25 (s, 1H), 8.12-7.93 (m, 1H), 6.58-6.35 (m, 1H), 4.84-4.58(m, 2H), 3.21-2.90 (m, 2H), 2.69 (s, 3H), 2.66-2.49 (m, 4H), 2.32 (s,3H), 1.81-1.59 (m, 4H), 1.54-1.39 (m, 2H).

Example 106 Synthesis of4-(4,4-difluoropiperidin-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidineStep 1.—Synthesis of4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine

To a stirred solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.2 g,1.29 mmol) in anh THF (10 mL) were sequentially added2-(piperidin-1-yl)ethanol (0.258 mL, 1.94 mmol) and triphenylphosphine(0.51 g, 1.94 mmol). The reaction mixture was cooled to 0° C. anddiisopropylazodicarboxylate (0.38 mL, 1.94 mmol) was added dropwise andthe mixture was stirred for 30 min. at 0° C. and kept overnight at 4° C.The solvent was removed at reduced pressure and the residue wasdissolved in DCM and washed with diluted HCl 1 N. The aqueous phase wasseparated, basified and extracted with DCM. The organic phase wasseparated, dried and the solvent was removed under reduced pressure togive a residue that was purified by flash chromatography eluting with(EtOAc/Petroleum ether, 8:2) to yield4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (146mg, 55 mmol, 42%) as an oil that solidifies “on standing”.

Step 2.—Synthesis of4-(4,4-difluoropiperidin-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine

A suspension of 4,4-difluoropiperidine hydrochloride (44 mg, 0.28 mmol)and potassium carbonate (78 mg, 0.56 mmol) in acetonitrile (3 mL) wasstirred for 15 min. Then,4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (50mg, 0.19 mmol) in acetonitrile (2 mL) was added to the mixture and wasstirred at room temperature overnight. The mixture was filtered and thesolvent was removed under reduced pressure to give4-(4,4-difluoropiperidin-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine(65 mg, 0.18 mmol, quantitative) as an oil. ¹H NMR (CDCl₃) δ ppm: 8.39(s, 1H), 7.95 (s, 1H), 4.62 (t, J=7.1 Hz, 2H), 4.11 (t, J=5.9 Hz, 4H),3.12-2.88 (m, 2H), 2.73-2.46 (m, 4H), 2.23-2.01 (m, 4H), 1.77-1.52 (m,4H), 1.52-1.37 (m, 2H).

Examples (107-110) were prepared following the same method as in example106

Ex. Structure Name NMR 107

4-(3,3-dimethylpyrrolidin- 1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d]pyrimidine ¹H NMR (CDCl₃, ca 1.2:1 rotamermixture ) δ ppm: 8.36/8.34 (2 x s, 1H), 7.93/7.90 (2 x s, 1H), 4.74-4.59(m, 2H), 3.95- 3.79 (m, 2H), 3.55/3.53 (2 x s, 2H), 3.33-3.03 (m, 2H),2.85-2.42 (m, 4H), 1.95/1.83 (2 x t, J = 7.1 Hz, 4H), 1.79-1.59 (m, 2H),1.55-1.39 (m, 2H), 1.22 (s, 3H), 1.18 (s, 3H). 108

4-(3-phenylpyrrolidin-1-yl)- 1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine ¹H NMR (CDCl₃, ca 1.2:1 rotamer mixture ) δppm: 8.26/8.24 (2 x s, 1H), 8.17/8.13 (2 x s, 1H), 7.44-7.31 (m, 4H),7.30- 7.22 (m, 1H), 4.57- 4.44 (m, 2H), 4.40-4.24 (m, 1H), 4.17-4.03 (m,1H), 4.04-3.83 (m, 1H), 3.83-3.53 (m, 2H), 2.93- 2.79 (m, 2H), 2.66-2.39 (m, 4H), 2.39-2.10 (m, 1H), 1.64-1.50 (m, 4H), 1.50-1.39 (m, 2H).109

N-methyl-1-(1-(2- (piperidin-1-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)pyrrolidin-3-amine ¹H NMR (CDCl₃) δ ppm: 8.36 (s, 1H), 7.92 (s,1H), 4.59 (t, J = 7.0 Hz, 2H), 4.16-3.30 (m, 5H), 3.19- 2.87 (m, 2H),2.69- 2.55 (m, 4H), 2.52 (s, 3H), 2.37-2.00 (m, 2H), 1.71- 1.52 (m, 4H),1.53-1.34 (m, 2H). 110

4-(piperidin-1-yl)-1-(2- (piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine ¹H NMR (CDCl₃) δ ppm: 8.34 (s, 1H), 7.93 (s,1H), 4.77-4.52 (m, 2H), 3.93 (t, J = 5.1 Hz, 4H), 3.23- 2.97 (m, 2H),2.79-2.44 (m, 4H), 1.94-1.54 (m, 10H), 1.54-1.37 (m, 2H).

Pharmacological Data

Brain membrane preparation and binding assays for the σ1-receptor wereperformed as described (DeHaven-Hudkins, D. L., L. C. Fleissner, and F.Y. Ford-Rice, 1992, Characterization of the binding of[³H]-(+)-pentazocine to 6 recognition sites in guinea pig brain, Eur. J.Pharmacol. 227, 371-378) with some modifications. Guinea pig brains werehomogenized in 10 vols. (w/v) of Tris-HCl 50 mM 0.32 M sucrose, pH 7.4,with a Kinematica Polytron PT 3000 at 15000 r.p.m. for 30 s. Thehomogenate was centrifuged at 1000 g for 10 min at 4° C. and thesupernatants collected and centrifuged again at 48000 g for 15 min at 4°C. The pellet was resuspended in 10 volumes of Tris-HCl buffer (50 mM,pH 7.4), incubated at 37° C. for 30 min, and centrifuged at 48000 g for20 min at 4° C. Following this, the pellet was resuspended in freshTris-HCl buffer (50 mM, pH 7.4) and stored on ice until use.

The radioligand used was [³H]-(+)-pentazocine at 5.0 nM and the finalvolume was 200 μl. The incubation was initiated with the addition of 100μA of membrane at a final tissue concentration of approximately 5 mgtissue net weight/mL and the incubation time was 150 m. at 37° C. Afterincubation, the membranes were collected onto pretreated glass fiberfilterplate (MultiScreen-FC, Millipore), with polyethylenimine 0.1%. Thefilters were washed two times with 200 μA of washing buffer (50 mM TrisCI, pH=7.4) and then 25 μl of Ecoscint H liquid scintillation cocktailwere added. Microplates were allowed to set for several hours and thenquantified by liquid scintillation spectrophotometry (1450 Microbeta,Wallac). Nonspecific binding was determined with 1 μM haloperidol.

Example % Displacement (10⁻⁶ M) K_(i) (nM) 1 97.2 9.2 4 96.4 12.7 5 90.350.6 6 78.6 73.1 7 54.7 291.5 9  49.50 699.7 11  94.10 24.4 13 61.4399.2 15 96.4 13.1 16 68.2 244.4 17 65.0 774.3 18 90.2 56.7 19 98.3 9.421 90.8 55.0 22 97.2 15.0 24 91.7 58.0 26 71.6 513.7 28 54.0 631.0 2996.5 16.4 31 76.8 573.0 32 63.3 683.2 34 71.7 155.9 35 97.5 11.1 36 n.a.54.6 38 n.a. 74.4 39 n.a. 115.7 41 n.a. 61.9 42 n.a. 32.7 44 n.a. 251.948 85.0 78.7 49 94.1 21.2 51 81.6 118.6 54 74.6 192.1 55 54.2 370.6 5664.5 181.5 60 76.0 141.5 61 25.9 805.0 62 93.4 41.4 64 91.4 108.4 6596.8 27.9 66 96.6 24.0 67 n.a. 29.0 68 n.a. 100.1 69 n.a. 23.4 73 n.a.102.4 74 n.a. 212.2 75 97.7 12.8 76 96.8 14.9 77 n.a. 6.7 78 n.a. 9.2 79n.a. 21.8 82 n.a. 12.2 83 n.a. 184.5 84 n.a. 813.5 85 n.a. 45.1 86 n.a.328.9 88 n.a. 946.1 93 n.a. 279.7 95 n.a. 85.2 101 n.a. 221.1 105 n.a.740.1

1. A compound of general formula I:

wherein R₁ and R₂ independently represent a hydrogen atom; a branched orunbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀; a substituted orunsubstituted cycloalkyl radical C₃₋₉; a branched or unbranchedcycloalkyl-alkyl radical C₁₋₁₀ group in which either the alkyl groupand/or the cycloalkyl group is optionally at least mono-substituted; asubstituted or unsubstituted cycloalkyl C₃₋₉ or cycloalkylalkyl C₁₋₁₀group in which the cycloalkyl group is condensed with anothersubstituted or unsubstituted mono- or polycyclic ring system; asubstituted or unsubstituted aryl radical; a substituted orunsubstituted, branched or unbranched arylalkyl radical C₁₋₁₀ or abenzhydryl group optionally monosubstituted; a substituted orunsubstituted heteroaryl radical; a substituted or unsubstituted,branched or unbranched heteroarylalkyl radical C₁₋₁₀; a substituted orunsubstituted non-aromatic heterocyclyl radical C₃₋₉; a substituted orunsubstituted, branched or unbranched heterocyclyl-alkyl radical C₁₋₁₀;a substituted or unsubstituted heterocyclyl C₃₋₉ or heterocyclyl-alkylradical C₁₋₁₀ group in which the heterocyclyl group is condensed withanother substituted or unsubstituted mono- or polycyclic ring system; orR₁ and R₂ together with the bridging nitrogen form a substituted orunsubstituted cycloalkyl radical C₃₋₉; a substituted or unsubstitutedheterocyclyl group C₃₋₉ or a substituted or unsubstituted heteroarylradical C₃₋₉; R₃ and R₄ independently represent a hydrogen atom; or an—COR₅; —C(O)NR₅R₆; —C(S)NR₅R₆; —SO₂R₇; —C(O)OR₅; —OR₅; —NR₅R₆;—NR₅C(O)R₆ or —NCR₅R₆; a branched or unbranched, saturated orunsaturated, optionally at least mono-substituted, aliphatic radicalC₁₋₁₀; a substituted or unsubstituted cycloalkyl radical C₃₋₉; abranched or unbranched cycloalkyl-alkyl radical C₁₋₁₀ group in whicheither the alkyl group and/or the cycloalkyl group is optionally atleast mono-substituted; a substituted or unsubstituted cycloalkyl C₃₋₉or cycloalkyl-alkyl C₁₋₁₀ group in which the cycloalkyl group iscondensed with another substituted or unsubstituted mono- or polycyclicring system; a substituted or unsubstituted aryl radical; a substitutedor unsubstituted, branched or unbranched arylalkyl radical C₁₋₁₀ or abenzhydryl group optionally monosubstituted; a substituted orunsubstituted heteroaryl radical; a substituted or unsubstituted,branched or unbranched heteroarylalkyl radical C₁₋₁₀; a substituted orunsubstituted non-aromatic heterocyclyl radical C₃₋₉; a substituted orunsubstituted, branched or unbranched heterocyclyl-alkyl radical C₁₋₁₀;a substituted or unsubstituted heterocyclyl C₃₋₉ or heterocyclyl-alkylradical C₁₋₁₀ group in which the heterocyclyl group is condensed withanother substituted or unsubstituted mono- or polycyclic ring system; orR₃ and R₄ together with the bridging nitrogen form a substituted orunsubstituted cycloalkyl radical C₃₋₉; a substituted or unsubstitutedheterocyclyl group C₃₋₉ or a substituted or unsubstituted heteroarylradical C₃₋₉; R₅, R₆ and R₇ independently represent a hydrogen atom; abranched or unbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀; a substituted orunsubstituted cycloalkyl radical C₃₋₉; a branched or unbranchedcycloalkyl-alkyl radical C₁₋₁₀ group in which either the alkyl groupand/or the cycloalkyl group is optionally at least mono-substituted; asubstituted or unsubstituted cycloalkyl C₃₋₉ or cycloalkyl-alkyl C₁₋₁₀group in which the cycloalkyl group is condensed with anothersubstituted or unsubstituted mono- or polycyclic ring system; asubstituted or unsubstituted aryl radical; a substituted orunsubstituted, branched or unbranched arylalkyl radical C₁₋₁₀ or abenzhydryl group optionally monosubstituted; a substituted orunsubstituted heteroaryl radical; a substituted or unsubstituted,branched or unbranched heteroarylalkyl radical C₁₋₁₀; a substituted orunsubstituted non-aromatic heterocyclyl radical C₃₋₉; a substituted orunsubstituted, branched or unbranched heterocyclyl-alkyl radical C₁₋₁₀;a substituted or unsubstituted heterocyclyl C₃₋₉ or heterocyclyl-alkylradical C₁₋₁₀ group in which the heterocyclyl group is condensed withanother substituted or unsubstituted mono- or polycyclic ring system; nis selected from 1, 2, 3 or 4; or a pharmaceutically acceptable salt,isomer, prodrug or solvate thereof.
 2. A compound according to claim 1where R₁ and R₂ independently represent a hydrogen atom; a branched orunbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀; or R₁ and R₂ together withthe bridging nitrogen form a substituted or unsubstituted cycloalkylradical C₃₋₉; a substituted or unsubstituted heterocyclyl group C₃₋₉ ora substituted or unsubstituted heteroaryl radical C₃₋₉ or apharmaceutically acceptable salt, isomer, prodrug or solvate thereof. 3.A compound according to claim 1 where R₃ and R₄ independently representa hydrogen atom; or an —COR₅; —C(O)NR₅R₆; —C(S)NR₅R₆; —SO₂R₇; or abranched or unbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀; or R₃ and R₄ together withthe bridging nitrogen form a substituted or unsubstituted cycloalkylradical C₃₋₉; a substituted or unsubstituted heterocyclyl group C₃₋₉ ora substituted or unsubstituted heteroaryl radical C₃₋₉ or apharmaceutically acceptable salt, isomer, prodrug or solvate thereof. 4.A compound according to claim 1 where R₅, R₆ and R₇ independentlyrepresent a hydrogen atom; a branched or unbranched, saturated orunsaturated, optionally at least mono-substituted, aliphatic radicalC₁₋₁₀; a substituted or unsubstituted cycloalkyl radical C₃₋₉; abranched or unbranched cycloalkyl-alkyl radical C₁₋₁₀ group in whicheither the alkyl group and/or the cycloalkyl group is optionally atleast mono-substituted; a substituted or unsubstituted cycloalkyl C₃₋₉or cycloalkyl-alkyl C₁₋₁₀ group in which the cycloalkyl group iscondensed with another substituted or unsubstituted mono- or polycyclicring system; a substituted or unsubstituted aryl radical; a substitutedor unsubstituted, branched or unbranched arylalkyl radical C₁₋₁₀ or atleast mono-substituted benzhydryl group; a substituted or unsubstitutedheteroaryl radical; a substituted or unsubstituted, branched orunbranched heteroarylalkyl radical C₁₋₁₀; a substituted or unsubstitutednon-aromatic heterocyclyl radical C₃₋₉; a substituted or unsubstituted,branched or unbranched heterocyclyl-alkyl radical C₁₋₁₀; a substitutedor unsubstituted heterocyclyl C₃₋₉ or heterocyclyl-alkyl radical C₁₋₁₀group in which the heterocyclyl group is condensed with anothersubstituted or unsubstituted mono- or polycyclic ring system or apharmaceutically acceptable salt, isomer, prodrug or solvate thereof. 5.A compound according to claim 1 where R₁ and R₂ independently representhydrogen atom; a branched or unbranched, saturated or unsaturated,optionally at least mono-substituted, aliphatic radical C₁₋₁₀; or whereR₁ and R₂ together with the bridging nitrogen form an optionally atleast monosubstituted group selected from:

where R_(a) independently represents a hydrogen, a branched orunbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀ or a (C═O)R′ group where R′represents a a linear or branched C₁₋₆-alkyl group, or apharmaceutically acceptable salt, isomer, prodrug or solvate thereof. 6.A compound according to claim 1 where R₃ and R₄ independently representa hydrogen atom; or an —COR₅; —C(O)NR₅R₆; —C(S)NR₅R₆; —SO₂R₇; or abranched or unbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀; or R₃ and R₄ together withthe bridging nitrogen form a group selected from:

where R_(b) independently represents a hydrogen, a halogen atom, aphenyl group, a branched or unbranched, saturated or unsaturated,optionally at least mono-substituted, aliphatic radical C₁₋₁₀ or a NHR′group where R′ represents a a linear or branched C₁₋₅-alkyl group;R′_(b) is a branched or unbranched, saturated or unsaturated, optionallyat least mono-substituted, aliphatic radical C₁₋₁₀ and m represents 1,2, 3 or 4, or a pharmaceutically acceptable salt, isomer, prodrug orsolvate thereof.
 7. A compound according to claim 1 where R₅, R₆ and R₇independently represent a hydrogen atom; a branched or unbranched,saturated or unsaturated, optionally at least mono-substituted,aliphatic radical C₁₋₁₀; or an optionally at least mono-substitutedgroup selected from:

where R_(c) independently represents a hydrogen, a halogen atom, an —OHor a branched or unbranched, saturated or unsaturated, optionally atleast mono-substituted, aliphatic radical C₁₋₁₀; or a pharmaceuticallyacceptable salt, isomer, prodrug or solvate thereof.
 8. A compoundaccording to claim 1 where R₁ and R₂ independently represent hydrogenatom; a branched or unbranched, saturated or unsaturated, optionally atleast mono-substituted, aliphatic radical C₁₋₁₀; or where R₁ and R₂together with the bridging nitrogen form an optionally at leastmono-substituted group selected from:

where R_(a) independently represents a hydrogen, a branched orunbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀ or a (C═O)R′ group where R′represents a a linear or branched C₁₋₆-alkyl group; R₃ and R₄independently represent a hydrogen atom; or an —COR₅; —C(O)NR₅R₆;—C(S)NR₅R₆ or —SO₂R₇; or R₃ and R₄ together with the bridging nitrogenform a group selected from:

where R_(b) independently represents a hydrogen, a halogen atom, aphenyl group, a branched or unbranched, saturated or unsaturated,optionally at least mono-substituted, aliphatic radical C₁₋₁₀ or a(C═O)R′ group where R′ represents a a linear or branched C₁₋₆-alkylgroup; R′_(b) is a branched or unbranched, saturated or unsaturated,optionally at least mono-substituted, aliphatic radical C₁₋₁₀ and mrepresents 1, 2, 3 or 4; R₅, R₆ and R₇ independently represent ahydrogen atom; a branched or unbranched, saturated or unsaturated,optionally at least mono-substituted, aliphatic radical C₁₋₁₀; or anoptionally at least mono-substituted group selected from:

where R_(c) independently represents a hydrogen, a halogen atom, an —OHor a branched or unbranched, saturated or unsaturated, optionally atleast mono-substituted, aliphatic radical C₁₋₁₀; n is selected from 1,2, 3 or 4; or a pharmaceutically acceptable salt, isomer, prodrug orsolvate thereof.
 9. A compound according to claim 1 selected from: [1]N-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamidemaleate [2]N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-naphthamide[3]2-fluoro-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide[4]N-(1-[2-(Piperidin-1-yl)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-adamantylcarboxamidemaleate [5]N-(1-(2-(Piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamidemaleate [6]N-(1-(2-(Piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexanecarboxamidehydrochloride [7]2,4-Dichloro-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamidehydrochloride [8]1,5-dimethyl-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride [9]3,5-di-tert-Butyl-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamidehydrochloride [10]2-hydroxy-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamidehydrochloride [11]N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)(1-noradamantylcarboxamide)maleate [12]N-(1-(2-Morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamidehydrochloride [13]N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamidehydrochloride [14]N-(1-(2-Morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexanecarboxamidehydrochloride [15]N-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexanecarboxamidemaleate [16]N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexanecarboxamidemaleate [17]N-(1-[2-(Morpholinoethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-adamantylcarboxamidehydrochloride [18]N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-adamantylcarboxamidemaleate [19]N-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)1-adamantylcarboxamide hydrochloride [20]N-(1-[2-(Morpholinoethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-noradamantylcarboxamidehydrochloride [21]N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-noradamantylcarboxamidehydrochloride [22]N-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)1-noradamantylcarboxamide hydrochloride [23]2,4-Dichloro-N-(1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamidehydrochloride [24]N-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2,4-dichlorobenzamidehydrochloride [25]2,4-Dichloro-N-(1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamidehydrochloride [26]N-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamidehydrochloride [27]N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamidehydrochloride [28]N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclopentanecarboxamidemaleate [29]N-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclopentanecarboxamidemaleate [30]N-(1-(2-(4-isopropylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamidemaleate [31]N-(1-(2-(4-isopropylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)1-adamantylcarboxamide maleate [32]N-(1-(2-(4-isopropylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclopentanecarboxamidemaleate [33]4-fluoro-N-(1-(2-(4-isopropylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamidemaleate [34]N-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-fluorobenzamidecitrate [35]N-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2,2,3,3-tetramethylcyclopropanecarboxamidecitrate [36]N-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4,4-difluorocyclohexanecarboxamidemaleate [37]N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclobutanecarboxamidemaleate [38]N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexanecarboxamidemaleate [39]N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclopentanecarboxamidemaleate [40]N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclopropanecarboxamidemaleate [41]N-(1-(4-(azepan-1-yl)butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamidemaleate [42]N-(1-(3-(azepan-1-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamidemaleate [43]N-(1-(24(3S,5R)-3,5-dimethylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide[44]1-(1-(2-(1,4-oxazepan-4-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea[45]1-tert-Butyl-3-(1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [46]1-Cyclohexyl-3-(1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [47]1-Adamanthyl-3-(1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [48]1-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-ethylureahydrochloride [49]1-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-cyclopentylureahydrochloride [50]1-(2,4-Dichlorophenyl)-3-(1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [51]1-(1-(2-(Azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-cyclohexylureahydrochloride [52]1-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-ethylureahydrochloride [53]1-Cyclopentyl-3-(1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [54]1-Cyclopentyl-3-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [55]1-Ethyl-3-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [56]1-Adamanthyl-3-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [57]1-Cyclohexyl-3-(1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [58]1-(2,4-Dichlorophenyl)-3-(1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [59]1-Cyclohexyl-3-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [60]1-(2,4-Dichlorophenyl)-3-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [61]1-tert-Butyl-3-(1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [62]1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-tert-butylureahydrochloride [63]1-Adamanthyl-3-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureamaleate [64]1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-(2,4-dichlorophenyl)ureacitrate [65]1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-(2,4,4-trimethylpentan-2-yl)ureamaleate [66]1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylureamaleate [67]1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-butylureahydrochloride [68]1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-cyclopropylureahydrochloride [69]1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-isopropylureahydrochloride [70]1-isopropyl-3-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [71]1-propyl-3-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ureahydrochloride [72]1-(1-(4-(azepan-1-yl)butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylureamaleate [73]1-(1-(3-(azepan-1-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea[74]1-(1-(2-(4-tert-butylpiperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea[75]1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-butylthioureamaleate [76]1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylthioureamaleate [77]1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylthiourea[78]1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-ethylthiourea[79]1-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-cyclopropylthioureahydrochloride [80]2,4-Dichloro-N-(1-(2-(diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzenesulfonamidehydrochloride [81]N-(1-(2-(Diisopropylamino)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexanesulfonamidehydrochloride [82]N-(1-(2-(4-tert-butylpiperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide[83]N-(1-(2-(1,4-oxazepan-4-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide[84]N-(1-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide[85]N-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide[86]N-(1-(3-(4-methylpiperazin-1-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide[87]N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide[88]N-(1-(4-(4-tert-butylpiperidin-1-yl)butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pivalamide[89]1-(1-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea[90]1-(1-(3-(4-methylpiperazin-1-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea[91]1-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea[92]1-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea[93]1-(1-(4-(4-tert-butylpiperidin-1-yl)butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea[94]1-(1-(2-(4-acetylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea[95]1-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-propylurea[96]2,4-dichloro-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzenesulfonamide[97]N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)methanesulfonamide[98]N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)propane-2-sulfonamide[99]]N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)cyclohexanesulfonamide[100]N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ethanesulfonamide[101]N-(1-(2-(azepan-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-methylacetamide[102]1-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyrrolidin-2-one[103]4-(1H-imidazol-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine[104]4-(1H-benzo[d]imidazol-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine[105]4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine[106]4-(4,4-difluoropiperidin-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine[107]4-(3,3-dimethylpyrrolidin-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine[108]4-(3-phenylpyrrolidin-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine[109]N-methyl-1-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyrrolidin-3-amine[110]4-(piperidin-1-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine10. A compound according to claim 1 for its use as a medicament.
 11. Acompound according to claim 9 for its use in the treatment of orprophylaxis of a sigma receptor mediated disease or condition or asanxiolytic or immunosuppressant.
 12. A compound according to claim 11wherein the disease is pain the disease is pain, especially neuropathicpain, inflammatory pain or other pain conditions involving allodyniaand/or hyperalgesia.
 13. A compound according to claim 10 for its use inthe treatment or prophylaxis of diarrhoea, lipoprotein disorders,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity,migraine, arthritis, hypertension, arrhythmia, ulcer, glaucoma,learning, memory and attention deficits, cognition disorders,neurodegenerative diseases, demyelinating diseases, addiction to drugsand chemical substances including cocaine, amphetamine, ethanol andnicotine; tardive diskinesia, ischemic stroke, epilepsy, stroke, stress,cancer, psychotic conditions, in particular depression, anxiety orschizophrenia; inflammation or autoimmune diseases.
 14. A process forthe preparation of a compound of general formula (Ia):

comprising the reaction between a compound of general formula (IX):

with a compound of general formula (X):

wherein R₁, R₂, R₄, R₅ and n have the meanings as in claim 1 and X is ahalogen.
 15. A process for the preparation of a compound of generalformula (Ib):

comprising the reaction between a compound of general formula (IX):

with a compound of general formula (XI):R₆NCZ  (XI) where R₁, R₂, R₆ and n have the meanings as in claim 1 and Zrepresents O or S.
 16. A process for the preparation of a compound ofgeneral formula (Ic):

comprising the reaction between a compound of general formula (IX):

with a compound of general formula (XII):R₇SO₂X  (XII) where R₁, R₂, R₇ and n have the meanings as in claim 1 andX represents a halogen.
 17. Process for the preparation of a compound ofgeneral formula formula (Id):

comprising de reaction between a compound of general formula (XIV):

with an heterocyclic compound of formula (XVI):

where R₁, R₂, and n have the meanings as in claim 1 and X is a halogen.18. Process for the preparation of a compound of general formula formula(Id″):

comprising the reaction of a compound of formula (VII):

with a 1,4-dione of formula (XIX):

where R₁, R₂ and n has the same meanings as in claim 1, where R_(b)independently represents a hydrogen, a halogen atom, a phenyl group, abranched or unbranched, saturated or unsaturated, optionally at leastmono-substituted, aliphatic radical C₁₋₁₀ or a NHR′ group and whereR′_(b) is a branched or unbranched, saturated or unsaturated, optionallyat least mono-substituted, aliphatic radical C₁₋₁₀.
 19. Process for thepreparation of a compound of general formula (I):

comprising the reaction between a compound of general formula (XIV):

with amines of formula R₃R₄NH (XVIII)

where R₁, R₂ R₃, R₄, and n have the same meanings as in claim 1 and X isa halogen.
 20. Process for the preparation of a compound of generalformula formula (Ie):

comprises de reaction between a compound of general formula (XIV):

with a compound of formula general (XVII):

where R₁, R₂, and n have the meanings as in claim 1, m is selected from1, 2, 3 or 4 and X is a halogen.
 21. A pharmaceutical compositioncomprising a compound of general formula (I) according to claim 1 or apharmaceutically acceptable salt, isomer, prodrug or solvate thereof,and at least a pharmaceutically acceptable carrier, additive, adjuvantor vehicle.